Methods for heart regeneration

ABSTRACT

Methods for heart regeneration are provided. The invention provided herein includes methods of modulating proliferation of cardiomyocytes using small molecules and micro RNAs. In embodiments, the methods provided may be used to increase proliferation or cardiomyocytes. Further provided are methods to be used for the treatment of myocardial infarction.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Appl. No. 61/712,701, filed Oct. 11, 2012, the contents of which are incorporated herein by reference and for all purposes.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant U01 HL107442-04 awarded by The National Heart, Lung and Blood Institute; the government has certain rights in the invention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII TEXT FILE

The Sequence Listing is submitted as an ASCII text file [9496002SequenceListing.txt,Jun. 8, 2015, 7.45 MB], which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

Heart failure remains one of the leading causes of mortality in the developed world. Whereas the mammalian heart is endowed with certain regenerative potential, endogenous cardiomyocyte proliferation is insufficient for functional heart repair upon injury. Interestingly, non-mammalian vertebrates, such as the zebrafish, can regenerate the damaged heart by inducing cardiomyocyte dedifferentiation and proliferation. By screening regenerating zebrafish hearts Applicants identified miR-99/100 down-regulation as a key process driving cardiomyocyte dedifferentiation. Experimental down-regulation of miR-99/100 in primary adult murine and human cardiomyocytes led to an increase in the number of proliferating cardiomyocytes. AAV-mediated in vivo down-regulation of miR-99/100 after acute myocardial injury in mice induced mature cardiomyocyte proliferation, diminished infarct size and improved heart function. Applicants' study unveils conserved regenerative mechanisms between zebrafish and mammalian cardiomyocytes and represents a proof-of-concept on the suitability of activating pro-regenerative responses for healing the diseased mammalian heart.

BRIEF SUMMARY OF THE INVENTION

In one aspect, a method of modulating proliferation of a cardiomyocyte is provided. The method includes (i) transfecting a cardiomyocyte with a nucleic acid encoding a micro RNA modulator, thereby forming a transfected cardiomyocyte; and (ii) allowing the transfected cardiomyocyte to divide, thereby modulating proliferation of the cardiomyocyte.

In another aspect, a method of modulating proliferation of a cardiomyocyte is provided. The method includes (i) contacting a cardiomyocyte with a small molecule, thereby forming a treated cardiomyocyte; and (ii) allowing the treated cardiomyocyte to divide, thereby modulating proliferation of the cardiomyocyte.

In another aspect, a method of treating myocardial infarction in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of a nucleic acid encoding a micro RNA modulator, wherein the RNA modulator increases cardiomyocyte proliferation thereby treating the myocardial infarction.

In another aspect, a method of treating myocardial infarction in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of a nucleic acid encoding an antagonist of a mir 99 micro RNA and a nucleic acid encoding an antagonist of a let-7a micro RNA, thereby treating the myocardial infarction.

In another aspect, a method of treating myocardial infarction in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of a small molecule, wherein the small molecule increases cardiomyocyte proliferation thereby treating the myocardial infarction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-J. miR-99/100 and Let-7a/c are involved in the early cardiac regenerative response in the zebrafish. (FIG. 1A) Amputated hearts were allowed to regenerate for 3 and 7 days, and then analyzed by real time RT-PCR for microRNA candidates miR-99/100 and Let-7a/c (n=8). (FIGS. 1B, C) FISH/double immunofluorescence was used to determine cardiomyocyte specific expression of microRNA-100 (n=5, see also FIG. 6) and its downstream targets fntβ (FIG. 1B) and smarca5 (FIG. 1C) in uninjured (left panel) and 7 dpa conditions (right panel). Cardiomyocytes in regenerating hearts exhibited remarkable low levels of both miRs, and inversely correlating high levels of Fntβ and Smarca5. (FIG. 1D) Gene expression fold change of fntβ and smarca5 in amputated hearts (n=8). (FIG. 1E) Chemical inhibition of fnt activity with Tipifarnib dramatically reduced cardiomyocyte proliferation and heart regeneration in amputated fish, leading to scarring as determined by Masson's Trichromic (FIG. 1F) staining and BrDU incorporation (FIG. 1G) (n=6). (FIGS. 1H, I, J) Knock-down of fntβ and/or smarca5 in embryos resulted in abnormally small animals and reduced ventricle size in cmlc2:GFP animals. The same phenotype was observed upon injection of miR-99/100 mimics (n>50). Dashed line: amputation plane. Boxed area: magnified field. Arrowheads: cells of interest.

FIGS. 2A-J. Heart regeneration in the fish is controlled by miR-99/100 and Let-7a/c. (FIG. 2A,B) Dedifferentiating cardiomyocytes express high levels of Fntβ (from top to bottom, uninjured, 3 dpa and 7 dpa, panel FIG. 2A) and Smarca5 (from top to bottom, uninjured, 3 dpa and 7 dpa, panel FIG. 2B) with a 3.5-fold and 7-fold protein increment at 7 dpa, respectively, (see histogram in FIGS. 2C, D; n=5). (FIGS. 2E, F, G) Exogenous intra-cardiac administration of miR-99/100 mimics led to defective cardiac regeneration, scarring and reduced cardiomyocyte proliferation (n=6). (FIG. 2H) miR-99/100 inhibitors exerted the opposite effect in uninjured adult animals, inducing significant cardiac hyperplasia (FIG. 2I) and increased ventricle size (FIG. 2J; n=6). Dashed line: amputation plane. Boxed area: magnified area. Ec: endocardial cells; cm: cardiomyocytes. Arrowheads: cells of interest.

FIGS. 3A-H. Adult mammalian cardiomyocytes can be directed to a proliferative state by forced silencing of the miR-99/100 cluster. Expression patterns of the miR-99/100 cluster during development in murine (FIG. 3A) and human cardiomyocytes (FIG. 3C) were determined by qRT-PCR (n=6). (FIGS. 3B, D) Dynamics of cardiomyocyte progenitor marker and Fntβ/Smarca5 expression during murine (FIG. 3B) and human (FIG. 3D) cardiac maturation. Both Fntβ and Smarca5 are up-regulated at cardiac progenitor stages, and strongly repressed in adult hearts (n=6). (FIGS. 3E, F) Cultured adult murine cardiomyocytes transduced with anti-miR-99/100+anti-Let-7 reverted to a dedifferentiated-like state, re-expressing GATA4 and dissembling the cytoskeleton (see also FIG. 17; n=3). (FIGS. 3G, H) Transduction with anti-miRs was sufficient to efficiently drive adult cardiomyocytes to a proliferative state (FIG. 3G), with beating functionality (FIG. 3H) (n=3).

FIGS. 4A-L. MicroRNA silencing is sufficient to induce heart regeneration in a murine model of myocardial infarction. (FIGS. 4A, B) Organotypic cultures of adult heart tissue were employed to study the effects of microRNA-99/100 and Let-7a/c silencing. (FIG. 4A) After 7 days of treatment, myocardial tissue became disorganized, with a loss of sarcomeric structures as determined by electron microscopy analysis (n=6). (FIG. 4B) Furthermore, re-expression of dedifferentiation markers was detected by immunofluorescence evaluation/quantification, as well as cardiomyocyte proliferation and FNTβ and SMARCA5 expression in normoxic and hypoxic conditions (n=6). (FIG. 4C) Representative pictures of echocardiography performed in control (left panel) and treated animals (right panel) at 18 days post-myocardial infarction (MI). In vivo silencing of miR-99/100 and Let-7 led to significant improvements in fractional shortening (FIGS. 4D, F) and ejection fraction (FIGS. 4E, F) at 18 days post-MI (n=5). (FIG. 4G) Left panel, reduced infarct size in miR-99/100 and Let-7 treated animals is confirmed by Masson's trichromic staining; (FIG. 4G) Right panel, quantification of scar size by Masson's thrichromic staining (FIG. 4G; n=5). (FIGS. 4H-J) Recovery was accompanied by cardiomyocyte-specific expression of FNTβ (FIG. 4H) and SMARCA5 (FIG. 4I), as well as GATA4 re-expression (FIG. 4J, right panel shows quantification of this data) as determined by immunofluorescence analyses (n=5). (FIGS. 4K, L, panel on the right shows quantification of this data) Regeneration was mediated by a dramatic increase in proliferating cardiomyocytes as determined by PCNA (FIG. 4K) and H3P (FIG. 4L) stainings (n=5). Arrowheads: cells of interest.

FIGS. 5A-C. miR-99/100 and Let-7a/c are located in same genomic cluster and their functions and protein targets are conserved across vertebrates. (FIG. 5A) Microarray analysis identified a subset of differentially regulated microRNAs during early stages of regeneration in the zebrafish heart (n=4). Interestingly, most of them were consistently down-regulated. (FIG. 5B) Bioinformatic analysis of the most relevant signaling pathways targeted by miR-99/100 and Let-7a/c. (FIG. 5C) Genomic organization and conservation of miR-99/100 and Let-7a/c clusters in vertebrates (upper left: zebrafish miR-100 cluster; upper right: zebrafish miR-99 cluster; lower left: human miR-99/100 clusters; lower right: murine miR-99/100 clusters).

FIGS. 6A-D. Expression of miR-99/100 is restricted to cardiomyocytes and inversely correlates with Fntβ and Smarca5. (FIGS. 6A-D) FISH/immunofluorescence analyses on zebrafish heart sections from uninjured and amputated animals at 3 and/or 7 dpa. (FIGS. 6A, B) FISH/immunofluorescence analysis of miR-100 and Fntβ/Smarca5 expression (see also FIG. 1; n=8). (FIGS. 6C, D) FISH/immunofluorescent analysis of miR-99 and Fntβ/Smarca5 expression during regeneration (upper row, miR-99 effects on Fntb expression at uninjured (left), 3 dpa (center) and 7 dpa (right) conditions; lower row, miR-99 effects on Smarca5 expression at uninjured (left), 3 dpa (center) and 7 dpa (right) conditions). (n=8). Dashed line: amputation plane. Boxed area: magnified in inset.

FIGs. 7A and 7B. Relevant protein targets of interest in heart regeneration regulated by miR-99/100 and Let-7a/c. (FIG.7A) For the Fntb 3′UTR, miR-100 (query) is SEQ ID NO: 1131, miR99 (query) is SEQ ID NO: 1132, and the reference sequences (Ref) are nucleotides 154-175 of SEQ ID NO: 1118 and 155-175 of SEQ ID NO: 1118, respectively. For the Smarca5 3′ UTR, miR-100 (query) is SEQ ID NO: 1131, miR-99 (query) is SEQ ID NO: 1132, and the reference sequences (Ref) are nucleotides 51-74 of SEQ ID NO: 1119 and 52-74 of SEQ ID NO: 1119, respectively. For Let-7a, the query is SEQ ID NO: 1136 and the reference sequence (Ref) is nucleotides 210 to 231 of SEQ ID NO: 1119. Miranda-based binding predictions of miR-99/100 to zebrafish Fntb (upper panel) and Smarca5 (lower panel) 3′ UTRs. (FIG.7B) Luciferase assay to determine biochemical binding of miR-99/100 to the predicted targets Fntb and Smarca5 for zebrafish (upper and middle rows) and human (lower row) 3′UTRs. Fish and human UTRs were subcloned in the pGL3 vector and subjected to microRNA mimic knockdown in vitro. pGL3: empty vector; AS-UTR: antisense-UTR (negative control); UTR: 3′untranslated region.

FIGS. 8A-B. Fntα, the structural subunit of Fnt, was constitutively expressed in cardiomyocytes regardless of regeneration conditions. Fntα expression was determined by immunofluorescence (FIG. 8A) and qRT-PCR (FIG. 8B, n=4). Dashed line: amputation plane. Boxed area: magnified section.

FIGS. 9A-D. MiR-99/100 plays a role in heart development. (FIG. 9A) Expression of miR-99/100 is very low during the first stages of development and dramatically increases at 3 dpf in zebrafish (n=10). (FIG. 9B) fntβ and smarca5 expression inversely correlate with miR-99/100 in developing embryos (n=10). (FIGS. 9C, D) Both Fntβ and Smarca5 are present at high levels in developing hearts (n=10). V: ventricle; A: atrium; Eb: erythroblasts.

FIGS. 10A-D. Targets of miR-99/100 and Let-7a/c return to basal levels of expression after cardiomyocytes come back to their quiescent state. (FIGS. 10A, B) Immunofluorescent stainings for proliferating cardiomyocytes at 30 dpa, when regeneration in the zebrafish heart is mostly complete (n=3). Fntβ and Smarca5 presence in the myocardium returned to pre-amputation levels at 30 dpa, when regeneration is mostly completed. (FIG. 10C) Strategy for the scarring experiments to identify the improtance in regeneration of miR-99/100. (FIG. 10D) Successful heart delivery of antagomiRs was evaluated by injection of a matched-size Cy5-labelled oligonucleotide against GFP in cmlc2:GFP animals (n=3). Dashed line: amputation plane. Boxed area: magnified section.

FIGS. 11A-B. Direct substrates of fnt are activated in regenerating hearts. (FIGS. 11A, B) At 3 and 7 dpa, a significant fraction of farnesylated proteins was detected in dedifferentiating cardiomyocytes as determined by immunofluorecence (n=5). Boxed area: magnified section.

FIGS. 12A-F. Signaling downstream of fntβ in the MAPK signaling pathway were consistently up-regulated in regenerating hearts. Ras (FIGS. 12A, B, C) and c-myc (FIGS. 12D, E, F), activators of the MAPK pathway regulated by miR-99/100 and Let-7a/c were up-regulated as determined by immunofluorescence (FIGS. 12A,D) and by qRT-PCR (FIGS. 12B,C,E,F; n=5). Dashed line: amputation plane. Boxed area: magnified section. Arrowheads: cells of interest.

FIGS. 13A-B. Chromatin remodeling is a necessary step in cardiomyocyte dedifferentiation. (FIGS. 13A,B) The chromatin remodeling agents Cbx5 (FIG. 13A) and Cbx3a (FIG. 13B), which act in concert with Smarca5, were found in the nucleus of dedifferentiating cardiomyocytes indicating a wave of chromatin remodeling. The following is shown in the histograms of FIG. 13A and FIG. 13B from left to right: First panel (bottom and top histogram): DAPI stain, second panel (bottom and top histogram): MyHC stain; third panel (bottom and top histogram): PCNA stain; forth panel (bottom and top histogram):Cbx5 stain; fifth panel (bottom and top histogram): merge of histograms of panels one, two three and four.(n=4). Arrowheads: cells of interest.

FIG. 14. Expression of miR-99/100 cluster is a switch to promote or inhibit cardiomyocyte dedifferentiation and proliferation in vertebrates. In the proposed model of action, quiescent cardiomyocytes express high levels of miR-99/100 and Let-7a/c, which inhibit the expression of key members of the proliferative activation cascade (Uninjured condition shown in left panel). Upon injury, cardiomyocytes cease to express these miRs, leading to the over-expression of key regulators of two parallel pathways simultaneously: MAPK signaling and chromatin remodeling (Injury condition shown in right panel). These changes lead to a proliferation-permissive state in cardiomyocytes, which become more receptive towards proliferative signals coming from the injured area and proliferate to replenish the lost tissue. The symbols “X” indicate blocked pathways.

FIGS. 15A-D. FISH/IF for different developmental stages in the mouse heart. (FIGS. 15A-C) Identical patterns of expression were found for miR-99/100 and Let-7a/c, as well as Fntβ and Smarca5, to those observed in the developing zebrafish (FIG. 15A: embryonic day 11; FIG. 15B: postnatal day 2; FIG. 15C: adult) (n=6). (FIG. 15D) Quantification showing the number of double positive cells for miR-99/100 (FIG. 15D upper left), Let-7a/c (FIG. 15D upper right), Fntβ (FIG. 15D lower left) and Smarca5 (FIG. 15D lower right) (n=6).

FIGS. 16A-B. Human ESC-derived, proliferation-competent immature cardiomyocytes (hiCM) possessed the same phenotype observed in fish and mouse dedifferentiated cardiomyocytes. (FIG. 16A) Immunofluorescence for the indicated proteins in human embryonic stem cells (FIG. 16A, Images are individual panels of the merged figure shown at in the last column). (FIG. 16B) hiCMs showed expression of GATA4, SMARCA5 and FNTβ, which was progressively lost with decreased proliferative capacity (n=3). The following is shown in the histograms of FIG. 16A and FIG. 16B from left to right: Histograms show immunostaining with DAPI (first panel), MyHC (second panel), GATA4 (third panel), SMARCA5 (forth panel top), FNTbeta (forth panel middle), of H3P (forth panel bottom) and a merged histogram (fifth panel).

FIGS. 17A-F. miR silencing leads to dedifferentiation and proliferation of cardiomyocytes. (FIG. 17A, Images represent individual panels of the merged image shown in the last column) Untreated adult murine cardiomyocytes spontaneously disorganized sarcomeric structures in vitro, but did not dedifferentiate or express FNTβ, SMARCA5, GATA4 or proliferative markers. However, upon lentiviral transduction with anti-Let-7 alone (FIG. 17B, Images represent individual panels of the merged image shown in the last column) or both anti-Let-7and anti-miR-99/100 (FIG. 17C, Images represent individual panels of the merged image shown in the last column) they re-expressed all those markers (n=3). (FIG. 17D) Functional beating properties were preserved in dedifferentiated cardiomyocytes, suggesting a degree of spontaneous redifferentiation, except for anti-Let-7 treatment. (FIGS. 17E, F) Cardiomyocyte dedifferentiation was evaluated by simultaneously measuring GATA4 and sarcomeric myosin expression and organization in cultured cardiomyocytes (n=3).

FIGS. 18A-C. microRNA silencing is specific for cardiomyocytes. (FIG. 18A) Human Fibroblasts (left panel) or endothelial cells (right panel) expressed basal levels of FNTβ, SMARCA5 and negligible levels of miR-99/100 and Let-7a/c (data not shown), and were insensitive to miR silencing (FIGS. 18A, B, C), indicating specificity of the treatment in a heart setting. (FIG. 18C) Images used for quantification of data shown in A and B (Images represent individual panels of the merged image shown in the last column) (n=3).

FIGS. 19A-B (from top to bottom, confocal analysis of FNTB, SMARCA5, Cx43, GATA4 and H3P). Histograms to the left represent positional information from the numbers shown in the insets. Ex vivo organotypic culture of murine myocardial tissue reveals sustained cardiomyocyte proliferation. Adult mouse heart tissue was cultured and treated with empty vector (pmiRZip), anti-miR-99/100 or both anti-miR-99/100 and anti-Let-7 (lentiviral activation was followed with a GFP reporter). Confocal analysis after 7 days of miR silencing led to significantly increased FNTβ and SMARCA5 (FIGS. 19A, B), enhanced numbers of dedifferentiated cardiomyocytes—determined by Cx43 and GATA4 expression—(FIG. 19B) and significantly increased number of proliferating cells (n=4). Dashed line and corresponding numbers: nuclear profile of representative cells. Boxed area: magnified section.

FIGS. 20A-E. Hypoxic injury in organotypic culture leads to increased dedifferentiation. (FIG. 20A) Schematic of hypoxia experiments. (FIG. 20B) Efficient lentiviral delivery was achieved in ex vivo conditions for all anti-miRs. (FIGS. 20C, D) Histomorphometric evaluation of the damaged myocardium in normoxic and hypoxic conditions by employing Masson's trichrome staining (n=4). (FIG. 20E) The dedifferentiation response was characterized by GATA4, Cx43, H3P, Fntβ and Smarca5 stainings (From top to bottom, Cx43, SMARCA5, H3P) (n=4). Dashed line: adjacent necrotic patch. Boxed area: magnified section. Dashed lines: necrotic tissue.

FIGS. 21A-B. Echocardiography showing functional improvement in infarcted mice treated with anti-miR-99/100 and anti-Let-7a (upper panel) and quantification of that data (lower panel). Animals were subjected to LAD artery ligation to provike infarction followed by tintramyocardial administration of antimiR containing AAV2/9 vectors. Functional heart recovery was measured versus untreated contrail animals. (FIG. 21A) At 18 dpi (days post infarction) mice treated with antimiR's exhibit a significant improvement in ejection fraction and fractional shortening, as well as reduction in scar size. (FIG. 21B) At 3 mpi (months post infarction) the improvements are still present (left panels, echocardiographic quantification; right panel, representative images), with further reduction of scar size and significant enlargement of the LAVW, indicative of replenishment of the myocardial mass.

FIGS. 22A-B. In vivo regenerative reprogramming by anti-miR delivery (FIG. 22A). In vivo-induced cardiomyocyte proliferation by anti-miR delivery (18 days post-infarction) (left panels, PCNA and H3P staining showing proliferating cardiomyocytes; right panel, quantification of the data) (FIG. 22B).

FIGS. 23A-B. In vivo dedifferentiation by anti-miR delivery. (FIG. 23A): left panel, GATA4 immunofluorescence; right panel, quantification of the data shown (FIG. 23B): histogram showing percentage of dedifferentiated CMs; (FIG. 23C): SMARCA5 immunofluorescence.

FIGS. 24A-B. Anti-miR99/100/let-7 delivery enhances functional recovery after infarction. Echocardiography measurements in infarcted animals treated with control vs. anti-miR treatment indicate significant regeneration after treatment (FIG. 24A). Quantification of those animals shows statistically significant functional recovery, both in farction shortening (left panel) as well as ejection fraction (right panel).

FIGS. 25A-B. Anti-miR99/100/let-7 delivery enhances functional recovery after infarction. Heart function improvement by anti-miR treatment is sustained over long periods of time (ejection fraction) and seems to involve regeneration of the myocardial mass (LAWV thickening, immunohistological analysis shown in FIG. 25A). Ultrasound analysis shown in FIG. 25B (abbreviations AW; anterior wall; ID: internal diameter; reflects heart dilation; PW: posterior wall).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

While various embodiments and aspects of the present invention are shown and described herein, it will be obvious to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, N.Y. 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, N.Y. 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

“Nucleic acid” refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form, and complements thereof. The term “polynucleotide” refers to a linear sequence of nucleotides. The term “nucleotide” typically refers to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA (including siRNA), and hybrid molecules having mixtures of single and double stranded DNA and RNA. The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, and 2-O-methyl ribonucleotides.

A “miRNA” or “microRNA” as provided herein refers to a nucleic acid that forms a double stranded RNA, which double stranded RNA has the ability to reduce or inhibit expression of a gene or target gene when expressed in the same cell as the gene or target gene. The complementary portions of the nucleic acid that hybridize to form the double stranded molecule typically have substantial or complete identity. In one embodiment, a microRNA refers to a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded miRNA. In embodiments, the miRNA inhibits gene expression by interacting with a complementary cellular mRNA thereby interfering with the expression of the complementary mRNA. Typically, the nucleic acid is at least about 15-50 nucleotides in length (e.g., each complementary sequence of the double stranded miRNA is 15-50 nucleotides in length, and the double stranded miRNA is about 15-50 base pairs in length). In other embodiments, the length is 20-30 base nucleotides, preferably about 20-25 or about 24-29 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

The words “complementary” or “complementarity” refer to the ability of a nucleic acid in a polynucleotide to form a base pair with another nucleic acid in a second polynucleotide. For example, the sequence A-G-T is complementary to the sequence T-C-A. Complementarity may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing.

The terms “protein”, “peptide”, and “polypeptide” are used interchangeably to denote an amino acid polymer or a set of two or more interacting or bound amino acid polymers. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.

The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

“Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence with respect to the expression product, but not with respect to actual probe sequences.

The terms “identical” or percent “identity,” in the context of two or more nucleic acids or proteins, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acids that are the same (i.e., about 60% identity, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection. See e.g., the NCBI web site at ncbi.nlm.nih.gov/BLAST. Such sequences are then said to be “substantially identical.” This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and/or additions, as well as those that have substitutions. Identity typically exists over a region that is at least about 50 amino acids or nucleotides in length, or over a region that is 50-100 amino acids or nucleotides in length, or over the entire length of a given sequence.

The term “gene” means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a “protein gene product” is a protein expressed from a particular gene.

The word “expression” or “expressed” as used herein in reference to a gene means the transcriptional and/or translational product of that gene. The level of expression of a DNA molecule in a cell may be determined on the basis of either the amount of corresponding mRNA that is present within the cell or the amount of protein encoded by that DNA produced by the cell (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, 18.1-18.88).

The term “recombinant” when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.

The term “heterologous” when used with reference to portions of a nucleic acid or protein indicates that the nucleic acid or protein comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

The term “exogenous” refers to a molecule or substance (e.g., nucleic acid or protein) that originates from outside a given cell or organism. Conversely, the term “endogenous” refers to a molecule or substance that is native to, or originates within, a given cell or organism.

A “vector” is a nucleic acid that is capable of transporting another nucleic acid into a cell. A vector is capable of directing expression of a protein or proteins encoded by one or more genes carried by the vector when it is present in the appropriate environment.

A “viral vector” is a viral-derived nucleic acid that is capable of transporting another nucleic acid into a cell. A viral vector is capable of directing expression of a protein or proteins encoded by one or more genes carried by the vector when it is present in the appropriate environment. Examples for viral vectors include, but are not limited to retroviral, adenoviral, lentiviral and adeno-associated viral vectors.

A “cell culture” is an in vitro population of cells residing outside of an organism. The cell culture can be established from primary cells isolated from a cell bank or animal, or secondary cells that are derived from one of these sources and immortalized for long-term in vitro cultures.

The terms “culture,” “culturing,” “grow,” “growing,” “maintain,” “maintaining,” “expand,” “expanding,” etc., when referring to cell culture itself or the process of culturing, can be used interchangeably to mean that a cell is maintained outside the body (e.g., ex vivo) under conditions suitable for survival. Cultured cells are allowed to survive, and culturing can result in cell growth, differentiation, or division. The term does not imply that all cells in the culture survive or grow or divide, as some may naturally senesce, etc. Cells are typically cultured in media, which can be changed during the course of the culture.

The terms “media” and “culture solution” refer to the cell culture milieu. Media is typically an isotonic solution, and can be liquid, gelatinous, or semi-solid, e.g., to provide a matrix for cell adhesion or support. Media, as used herein, can include the components for nutritional, chemical, and structural support necessary for culturing a cell.

The term “derived from,” when referring to cells or a biological sample, indicates that the cell or sample was obtained from the stated source at some point in time. For example, a cell derived from an individual can represent a primary cell obtained directly from the individual (i.e., unmodified), or can be modified, e.g., by introduction of a recombinant vector, by culturing under particular conditions, or immortalization. In some cases, a cell derived from a given source will undergo cell division and/or differentiation such that the original cell is no longer exists, but the continuing cells will be understood to derive from the same source.

The term “transfection” or “transfecting” is defined as a process of introducing a nucleic acid molecule to a cell using non-viral or viral-based methods. The nucleic acid molecule can be a sequence encoding complete proteins or functional portions thereof. Typically, a nucleic acid vector, comprising the elements necessary for protein expression (e.g., a promoter, transcription start site, etc.). Non-viral methods of transfection include any appropriate transfection method that does not use viral DNA or viral particles as a delivery system to introduce the nucleic acid molecule into the cell. Exemplary non-viral transfection methods include calcium phosphate transfection, liposomal transfection, nucleofection, sonoporation, transfection through heat shock, magnetifection and electroporation. For viral-based methods, any useful viral vector can be used in the methods described herein. Examples of viral vectors include, but are not limited to retroviral, adenoviral, lentiviral and adeno-associated viral vectors. In some aspects, the nucleic acid molecules are introduced into a cell using a retroviral vector following standard procedures well known in the art.

Expression of a transfected gene can occur transiently or stably in a host cell. During “transient expression” the transfected nucleic acid is not integrated into the host cell genome, and is not transferred to the daughter cell during cell division. Since its expression is restricted to the transfected cell, expression of the gene is lost over time. In contrast, stable expression of a transfected gene can occur when the gene is co-transfected with another gene that confers a selection advantage to the transfected cell. Such a selection advantage may be a resistance towards a certain toxin that is presented to the cell. Expression of a transfected gene can further be accomplished by transposon-mediated insertion into to the host genome. During transposon-mediated insertion, the gene is positioned in a predictable manner between two transposon linker sequences that allow insertion into the host genome as well as subsequent excision.

The terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance that results in a detectably lower expression or activity level as compared to a control. The inhibited expression or activity can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or less than that in a control. In certain instances, the inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more in comparison to a control.

The terms “therapy,” “treatment,” and “amelioration” refer to any reduction in the severity of symptoms, e.g., of a neurodegenerative disorder or neuronal injury. As used herein, the terms “treat” and “prevent” are not intended to be absolute terms. Treatment can refer to any delay in onset, amelioration of symptoms, improvement in patient survival, increase in survival time or rate, etc. The effect of treatment can be compared to an individual or pool of individuals not receiving the treatment, or to the same patient prior to treatment or at a different time during treatment. In some aspects, the severity of disease is reduced by at least 10%, as compared, e.g., to the individual before administration or to a control individual not undergoing treatment. In some aspects the severity of disease is reduced by at least 25%, 50%, 75%, 80%, or 90%, or in some cases, no longer detectable using standard diagnostic techniques.

The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate a given disorder or symptoms. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.

“Subject,” “patient,” “individual in need of treatment” and like terms are used interchangeably and refer to, except where indicated, mammals such as humans and non-human primates, as well as rabbits, rats, mice, goats, pigs, and other mammalian species. The term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under medical supervision.

Methods of Modulating Cardiomyocyte Proliferation

Provided herein are methods of modulating proliferation of a cardiomyocyte using micro RNA modulators. A micro RNA modulator as used herein refers to an agent capable of modulating the level of expression of a micro RNA (e.g. let-7a, mir 100). In some embodiments, the micro RNA modulator is encoded by a nucleic acid. In other embodiments, the micro RNA modulator is a small molecule (e.g. a chemical compound, synthetic micro RNA molecule). In some embodiments, the micro RNA modulator decreases the level of expression of a micro RNA compared to the level of expression in the absence of the micro RNA modulator. Where the micro RNA modulator decreases the level of expression of a micro RNA relative to the absence of the modulator, the micro RNA modulator is an antagonist of said micro RNA. In other embodiments, the micro RNA modulator increases the level expression of a micro RNA compared to the level of expression in the absence of the micro RNA modulator. Where the micro RNA modulator increases the level of expression of a micro RNA relative to the absence of the modulator, the micro RNA modulator is an agonist of the micro RNA.

In one aspect, a method of modulating proliferation of a cardiomyocyte is provided. The method includes (i) transfecting a cardiomyocyte with a nucleic acid encoding a micro RNA modulator, thereby forming a transfected cardiomyocyte; and (ii) allowing the transfected cardiomyocyte to divide, thereby modulating proliferation of the cardiomyocyte. In some embodiments, the nucleic acid is a lentiviral vector. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1124 or SEQ ID NO:1125. In some embodiments, the nucleic acid is a lentiviral vector. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1124 and SEQ ID NO:1125. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1124. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1125. In embodiments, the nucleic acid has the sequence as set forth in SEQ ID NO:1124 or SEQ ID NO:1125. In embodiments, the nucleic acid has the sequence as set forth in SEQ ID NO:1124. In embodiments, the nucleic acid has the sequence as set forth in SEQ ID NO:1125.

In other embodiments, the micro RNA modulator is an antagonist of a mir 99 micro RNA, a let-7a micro RNA, a mir 100 micro RNA, a mir 4458 micro RNA, a mir 4500 micro RNA or a mir 89 micro RNA. In some embodiments, the proliferation of the cardiomyocyte is increased compared to a control cardiomyocyte lacking the nucleic acid encoding said RNA modulator. In some embodiments, the micro RNA modulator is an agonist of a mir 99 micro RNA, a let-7a micro RNA, a mir 100 micro RNA, a mir 4458 micro RNA, a mir 4500 micro RNA or a mir 89 micro RNA.

In another aspect, a method of modulating proliferation of a cardiomyocyte is provided. The method includes (i) contacting a cardiomyocyte with a small molecule, thereby forming a treated cardiomyocyte; and (ii) allowing the treated cardiomyocyte to divide, thereby modulating proliferation of the cardiomyocyte. In some embodiments, the proliferation of the cardiomyocyte is increased compared to a control cardiomyocyte lacking the small molecule. In some further embodiment, the small molecule modulates expression of a mir 99 micro RNA-regulated protein, a let-7a micro RNA-regulated protein, a mir 100 micro RNA-regulated protein, a mir 4458 micro RNA-regulated protein, a mir 4500 micro RNA-regulated protein or a mir 89 micro RNA-regulated protein. In other embodiments, the small molecule is a chemical compound. In some embodiments, the small molecule is a synthetic micro RNA molecule. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth in SEQ ID NO:1124 or SEQ ID NO:1125. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth in SEQ ID NO:1124 and SEQ ID NO:1125. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth in SEQ ID NO:1124. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth in SEQ ID NO:1125. In embodiments, the synthetic micro RNA molecule has a nucleic acid sequence as set forth in SEQ ID NO:1124. In embodiments, the synthetic micro RNA molecule has a nucleic acid sequence as set forth in SEQ ID NO:1125.

In other embodiments, the proliferation of the cardiomyocyte is increased compared to a control cardiomyocyte lacking the synthetic micro RNA molecule. In some embodiments, the synthetic micro RNA molecule is an antagonist of a mir 99 micro RNA, a let-7a micro RNA, a mir 100 micro RNA, a mir 4458 micro RNA, a mir 4500 micro RNA or a mir 89 micro RNA. In other embodiments, the synthetic micro RNA molecule is an agonist of a mir 99 micro RNA, a let-7a micro RNA, a mir 100 micro RNA, a mir 4458 micro RNA, a mir 4500 micro RNA or a mir 89 micro RNA.

In another aspect, a method of treating myocardial infarction in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of a nucleic acid encoding a micro RNA modulator, wherein the RNA modulator increases cardiomyocyte proliferation thereby treating the myocardial infarction. In some embodiments, the micro RNA modulator is an antagonist of a mir 99 micro RNA, a let-7a micro RNA, a mir 100 micro RNA, a mir 4458 micro RNA, a mir 4500 micro RNA or a mir 89 micro RNA. In embodiments, the micro RNA modulator is an antagonist of a mir 99 micro RNA and an antagonist of a let-7a micro RNA. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1124 or SEQ ID NO:1125. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1124. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1125. In embodiments, the nucleic acid includes a nucleic acid sequence as set forth in SEQ ID NO:1124 and SEQ ID NO:1125.

In embodiments, the method includes administering to the subject a therapeutically effective amount of a first nucleic acid and a second nucleic acid, wherein the first nucleic acid encodes an antagonist of a mir 99 micro RNA and the second nucleic acid encodes an antagonist of a let-7a micro RNA. In embodiments, the administering to the subject a therapeutically effective amount of a nucleic acid includes administering a first nucleic acid and a second nucleic acid, wherein the first nucleic acid encodes an antagonist of a mir 99 micro RNA and the second nucleic acid encodes an antagonist of a let-7a micro RNA.

In another aspect, a method of treating myocardial infarction in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of a nucleic acid encoding an antagonist of a mir 99 micro RNA and a nucleic acid encoding an antagonist of a let-7a micro RNA, thereby treating the myocardial infarction.

In another aspect, a method of treating myocardial infarction in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of a small molecule, wherein the small molecule increases cardiomyocyte proliferation thereby treating the myocardial infarction. In some embodiments, the small molecule modulates expression of a mir 99 micro RNA-regulated protein, a let-7a micro RNA-regulated protein, a mir 100 micro RNA-regulated protein, a mir 4458 micro RNA-regulated protein, a mir 4500 micro RNA-regulated protein or a mir 89 micro RNA-regulated protein. In embodiments, the small molecule modulates expression of a mir 99 micro RNA-regulated protein and a let-7a micro RNA-regulated protein. In some other embodiments, the small molecule is a chemical compound. In other embodiments, the small molecule is a synthetic micro RNA molecule. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth by SEQ ID NO:1124 or SEQ ID NO:1125. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth by SEQ ID NO:1124 and SEQ ID NO:1125. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth by SEQ ID NO:1124. In embodiments, the synthetic micro RNA molecule includes a nucleic acid sequence as set forth by SEQ ID NO:1125. In some embodiments, the synthetic micro RNA molecule is an antagonist of a mir 99 micro RNA, a let-7a micro RNA, a mir 100 micro RNA, a mir 4458 micro RNA, a mir 4500 micro RNA or a mir 89 micro RNA.

EXAMPLES

Heart failure remains one of the leading causes of mortality in the developed world. Whereas the mammalian heart is endowed with certain regenerative potential, endogenous cardiomyocyte proliferation is insufficient for functional heart repair upon injury. Interestingly, non-mammalian vertebrates, such as the zebrafish, can regenerate the damaged heart by inducing cardiomyocyte dedifferentiation and proliferation. By screening regenerating zebrafish hearts Applicants identified miR-99/100 down-regulation as a key process driving cardiomyocyte dedifferentiation. Experimental down-regulation of miR-99/100 in primary adult murine and human cardiomyocytes led to an increase in the number of proliferating cardiomyocytes. AAV-mediated in vivo down-regulation of miR-99/100 after acute myocardial injury in mice induced mature cardiomyocyte proliferation, diminished infarct size and improved heart function. Applicants' study unveils conserved regenerative mechanisms between zebrafish and mammalian cardiomyocytes and represents a proof-of-concept on the suitability of activating pro-regenerative responses for healing the diseased mammalian heart.

Cardiovascular disease remains the leading cause of mortality in the developed world. Attempts at developing curative strategies have mainly focused on the activation of endogenous cardiac progenitor cells and the transplantation of in vitro-derived cardiomyocytes (A. Aguirre et al., Cell Stem Cell 12, 275-284 (2013); S. R. Braam et al., Trends in pharmacological sciences 30, 536-45 (2009)). More recently, in vivo reprogramming strategies have emerged as potential treatments for heart failure (L. Qian et al., Nature (2012), doi:10.1038/nature11044; K. Song et al., Nature 485, 599-604 (2012) A. Eulalio et al., Nature (2012), doi:10.1038/nature11739). Along this line, a recent report by Porrello et al. has highlighted a remarkable regenerative capacity in neonatal murine hearts upon injury (E. R. Porrello et al., Science (New York, N.Y.) 331, 1078-80 (2011)). Although adult mammalian cardiomyocytes retain a certain ability to proliferate (S. E. Senyo et al., Nature, 2-6 (2012)), endogenous regenerative responses during adulthood are largely insufficient for replenishing the lost cardiac tissue. Noticeably, heart repair can be induced upon manipulation of miRNA pathways identified as drivers of cardiomyocyte proliferation in neonatal murine models (A. Eulalio et al., Nature (2012), doi:10.1038/nature11739L; E. R. Porrello et al., Circulation research 109, 670-9 (2011)). This may suggest that the mechanisms underlying heart regeneration at birth are still present, yet dormant and/or repressed, in adult murine hearts. Other vertebrates, such as the zebrafish, are able, throughout their entire lifetime, to activate endogenous regenerative responses that lead to complete cardiomyocyte-mediated heart regeneration similar to that observed in neonatal mice (R. Zhang et al., Nature (2013), doi:10.1038/nature12322; K. D. Poss et al., Science (New York, N.Y.) 298, 2188-90 (2002); A. Raya et al., Proceedings of the National Academy of Sciences of the United States of America 100 Suppl, 11889-95 (2003); C. Jopling et al., Nature 464, 606-9 (2010); K. Kikuchi et al., Nature 464, 601-5 (2010)). Together, these observations led us to hypothesize on the existence of conserved pro-regenerative pathways between zebrafish and mammals (A. W. Seifert et al., Nature 489, 561-5 (2012)), and if present, whether they could be altered to drive terminally differentiated mammalian cardiomyocytes to a regeneration-competent state.

To first elucidate the presence of conserved regulatory pathways underlying regeneration Applicants decided to focus on microRNAs promoting cardiomyocyte dedifferentiation in the zebrafish. Expression of 90 microRNAs was significantly changed 3 days post amputation (dpa) of the ventricular apex (FIG. 5A). Bioinformatic analysis of signaling pathways and GO processes indicated significant enrichment in proliferation pathways, as well as processes related to chromatin remodeling (S. L. Paige et al., Cell 151, 221-32 (2012)), morphogenesis and kinase activity (FIG. 5B). Interestingly, two well-defined down-regulated microRNA clusters (miR-99/Let-7a and miR-100/Let-7c) were highly conserved in sequence and genomic organization across different vertebrates (FIG. 5C). Putative protein targets were also shared between zebrafish and mammals (Table S1 and Table S2). Further expression analysis demonstrated a significant down-regulation of miR-99/100 and Let-7a/c during the early regenerative stages (3-7 dpa) (FIG. 1A) in agreement with previous reports (C. Jopling et al., Nature 464, 606-9 (2010)). Noticeably, miR-99/100 and Let-7a/c expression (data not shown) was high and confined to cardiomyocytes in uninjured hearts, and almost undetectable upon injury (FIG. 1, B and C and FIG. 6). microRNA target prediction highlighted two proteins specifically expressed in the regenerating zebrafish heart, Fntβ (beta subunit of farnesyl-transferase) and Smarca5 (SWI/SNF-related matrix associated actin-dependent regulator of chromatin subfamily a, member 5) (FIG. 1, B to D and FIG. 6). Binding experiments confirmed miRNA targeting of the 3′UTRs in both human and zebrafish Fntβ and Smarca5 (a C. Mueller et al., 2H., Oncogene, 1-9 (2012)) (FIG. 7). Accompanying Fntβ up-regulation, the structural subunit of fnt (Fntα) was also expressed during heart regeneration (FIG. 8). Chemical inhibition of fnt with the specific antagonist tipifarnib significantly impaired heart regeneration by decreasing the number of proliferating cardiomyocytes (FIG. 1, E to G). Taken together, these data suggest that targets downstream of miR-99/100 play a functional role during heart regeneration.

Since regeneration might be considered to a large extent redolent of development (J. P. Brockes, A. Kumar, Annual review of cell and developmental biology 24, 525-49 (2008); J. L. Whited, C. J. Tabin, 2-4 (2010); D. Knapp, E. M. Tanaka, Current Opinion in Genetics & Development (2012), doi:10.1016/j.gde.2012.09.006) Applicants next decided to investigate the role of miR-99/100 and their target proteins Fntβ and Smarca5 during zebrafish heart development and maturation. qRT-PCR and immunofluorescence analyses demonstrated low levels of miR-99/100 expression during early heart development concomitantly with high levels of Smarca5 and Fntβ (FIG. 9). Functional analyses by injection of miR-99/100 mimics, and/or fntβ/smarca5 translation-blocking morpholinos in one-cell stage cmlc2:GFP transgenic fish embryos resulted in a significantly reduced ventricle size in spite of the presence of apparently normal heart anatomical structures (ventricle, atrium, valve) (FIG. 1, H to J). To determine if cardiomyocytes showing up-regulation of Fntβ and Smarca5 progress into a proliferative state, Applicants analyzed the expression of nuclear proliferative markers at different time points post-amputation (FIG. 2, A to D). In all cases high levels of Fntβ and Smarca5 correlated with PCNA and/or H3P expression in the nucleus. Concomitantly, disorganized sarcomeric structures were particularly evident at 7 dpa (FIG. 2, A and B). miR-99/100 expression levels, and their respective protein targets, returned to basal levels when regeneration of the ventricle was mostly complete at 30 dpa (FIG. 10, A and B). Next, Applicants designed a series of in vivo experiments to exogenously manipulate miR-99/100 levels with mimics and antagomiRs in adult regenerating animals (FIG. 10, C and D). Intra-cardiac injection of miR-99/100 mimics efficiently blocked the regenerative response in all animals tested (FIG. 2, E and F) and BrdU incorporation confirmed that cardiomyocyte proliferation was significantly disrupted in mimic-treated animals (FIG. 2G). Conversely, microRNA inhibition of size-matched sibling fish led to significantly enlarged hearts (FIG. 2, H and I). Histological analysis indicated cardiomyocyte proliferation in the absence of cardiac hypertrophy (FIG. 2J), suggesting hyperplasia as the underlying mechanism of action of miRNA-99/100. Applicants next decided to study the downstream signaling mechanisms of miR-99/100 and Let-7a/c. Applicants detected increased farnesylation as a consequence of fnt activity in regenerating hearts at 3 and 7 dpa (FIG. 11). Ras family proteins, targets of fnt, appeared up-regulated and preferentially located to the cell membrane (FIG. 12, A to C). Similarly, c-Myc, a transcription factor essential for cellular proliferation downstream of this pathway, was significantly up-regulated and localized to the cell nucleus in dedifferentiating cardiomyocytes (FIG. 12, D to F). Interestingly, Cbx5 and Cbx3a, chromatin-remodeling proteins critical in proliferating cardiomyocytes (J. K. Takeuchi et al., Nature communications 2, 187 (2011); N. Collins et al., Nature genetics 32, 627-32 (2002); S. H. Kwon, J. L. Workman, BioEssays: news and reviews in molecular, cellular and developmental biology 33, 280-9 (2011)), demonstrated enhanced expression at 7 dpa, when Smarca5 levels in the nucleus were highest (FIG. 13). Taken together, Applicants' results indicate that miR-99/100 down-regulation plays a role, possibly by chromatin remodeling, in the dedifferentiation process that leads to zebrafish heart regeneration (FIG. 14).

In light of the evolutionary conservation of their structures and downstream signaling pathways, Applicants wondered whether microRNA-99/100 and Let-7a/c functions would be similar between mammals and zebrafish. To this end, Applicants first analyzed microRNA-99/100 and FNTβ/SMARCA5 expression in developing and adult murine hearts. qRT-PCR and immunofluorescence analyses highlighted a progressive up-regulation of microRNA-99/100 paralleling cardiac maturation and FNTβ/SMARCA5 down-regulation (FIG. 3, A and B and FIG. 15). Analyses of human cardiomyocytes at progressive differentiation stages, including adult heart samples, demonstrated a peak in miR-99/100 expression in adult mature human cardiomyocytes, a point at which FNTβ/SMARCA5 expression was undetectable (FIG. 3, C and D). hESC-derived immature proliferative cardiomyocytes (hiCM) expressed GATA4 (a cardiac progenitor marker), FNTβ, SMARCA5 and intermediate-low levels of the identified miRNAs (FIG. 16) resembling a regenerative, proliferative state as described before (K. Kikuchi et al., Nature 464, 601-5 (2010), C. Jopling et al., Nature reviews. Molecular cell biology 12, 79-89 (2011)).

Applicants next sought to evaluate the effects of microRNA down-regulation in adult murine cardiomyocytes. Seven days after shRNA-mediated microRNA silencing significant up-regulation of SMARCA5 and FNTβ was observed accompanied by an increased amount of cardiomyocytes with disorganized sarcomeric structures and immature morphology (FIG. 3, E and F and FIG. 17, A to C). Further analysis demonstrated enhanced proliferation paralleling GATA4 and PCNA re-expression (FIG. 3, E to G and FIG. 17). These effects were more pronounced when miR-99/100 and Let-7a/c were simultaneously blocked (FIG. 3G and FIG. 17). Similarly, microRNA silencing in human cardiomyocytes resulted in increased proliferation and higher numbers of beating colonies (FIG. 3, G and H and Videos 1 to 5). Functional analyses demonstrated minimal changes in the beating rate before and after anti-miR delivery (FIG. 17D). Indicative of cardiomyocyte specificity, microRNA down-regulation did not affect proliferation or FNTβ/SMARCA5 expression in human fibroblasts or vascular cells (FIG. 18). Organotypic cultures of adult murine hearts, a setting more closely resembling physiological conditions (M. Brandenburger et al., Cardiovascular research 93, 50-9 (2012)), demonstrated low to undetectable levels of FNTβ/SMARCA5 (FIG. 19). Delivery of anti-miR-99/100 and/or anti-miR-Let-7 to murine heart organotypic slices resulted in cardiomyocyte proliferation as demonstrated by down-regulation of MyHC as well as re-expression of GATA4 and H3 phosphorylation (FIG. 19). Ultrastructural electron microscopy analysis confirmed cytoskeletal disassembly (FIG. 4A). Further supporting these observations, Connexin 43 (Cx43), an essential component of coupling GAP junctions in cardiomyocytes, was profoundly down-regulated (FIG. 19). Next, Applicants mimicked tissue ischemia and heart damage in organotypic slices to determine the effects of the treatment upon injury (FIG. 20A). Control organotypic slices developed necrotic areas accompanied by marginal proliferation under hypoxic conditions whereas anti-microRNA delivery resulted in reduced necrosis (FIG. 20B to D) and the appearance of proliferative cardiomyocyte populations (FIG. 4B and FIG. 20D).

Lastly, Applicants decided to test the efficacy of anti-microRNA delivery for the induction of regeneration in a murine model of myocardial infarction. Following LAD artery ligation, anti-miR-99/100 and anti-Let-7 were administered by injection of serotype 9 adeno-associated viral (AAV) particles, specifically targeting the cardiomyocyte population, in the periphery of the infarcted area. 18 days after treatment, both ejection fraction and fractional shortening significantly improved in the treated group (FIG. 4, C to F). Reduced fibrotic scarring and infarct sizes were readily observed three weeks after LAD artery ligation, indicative of an underlying regenerative response (FIG. 4G). Treated animals exhibited increased numbers of FNTβ/SMARCA5 positive cardiomyocytes, as well as a marked increase of cardiomyoctes re-expressing GATA4. PCNA and H3P staining demonstrated increased DNA synthesis and cardiomyocyte mitosis (FIG. 4, H to L). Of note, the number of mitotic cardiomyocytes was higher in areas of trabeculated muscle as opposed to the myocardium proper. Taken together, all these observations indicate that anti-miR delivery in adult murine cardiomyocytes suffices for the induction of a pro-regenerative proliferative response towards repairing a damaged heart.

These observations constitute a proof-of-concept on how animal models naturally capable of regeneration can be used for the identification of regenerative factors that may, subsequently, be applied to mammals. Experimental manipulation of conserved microRNAs unveiled during adult zebrafish heart regeneration led to similar responses in mice after heart infarction (replenishment of the lost cardiac tissue and inhibition of scar formation). In vivo activation of conserved cardiac regenerative responses may help to circumvent many of the problems associated with heart cell transplantation as well as those associated with reprogramming technologies (A. Aguirre et al., Cell Stem Cell 12, 275-284 (2013), M. a. Laflamme, C. E. Murry, Nature 473, 326-335 (2011)), serving as an additional tool to the clinical armamentarium of regenerative medicine towards the treatment of human heart disease (K. R. Chien et al., Journal of molecular and cellular cardiology 53, 311-3 (2012)).

Experimental Procedures

Detailed experimental procedures can be found in Supplementary information.

Animals. Wild-type zebrafish (AB) and cmlc2:GFP were maintained at 28.5° C. by standard methods, unless otherwise indicated. All protocols were previously approved and performed under institutional guidelines.

Culture and isolation of adult mouse ventricular myocytes. Wild-type mice (C57B6/J) were sacrificed and hearts were quickly recovered and washed with ice-cold Ca²⁺-free ModifiedTyrode's Solution (MTS). Ventricles were dissected from the rest of the heart and subjected to enzymatic digestion (Liberase DH, Roche) for 10-15 min in a spinner flask at 37 C under continuous agitation. Afterwards cells were pelleted by short centrifugation, resuspended in KB solution and cardiomyocytes were left to sediment by gravity, thus greatly reducing the presence of other contaminating cell types. Calcium was restore to 1 mM in a step-wise fashion in three gradual steps and subsequently cardiomyocytes were centrifuged, resuspended in culture medium (IMDM 5%, 1% Pen/Strep, 0.1 ng/ml FGFb, 1 ng/ml TGF-β3) and seeded in laminin-coated tissue-culture plates. Cells were kept in culture for 1 week.

Lentiviral and AAV constructs. Anti-miR constructs, miRZip-99/100 and miRZip-let7 (SBI), were used according to the manufacturer instructions. As respective controls, the anti-miRs were removed from the parent vector by digesting with BamHI and EcoRI, end filled and re-ligated. Lentiviruses were packaged by transfecting in 293T cells followed by spinfection in the respective mouse or human ES derived cardiomyocytes. AAVs were generated as described before (Eulalio et al, 2012). Briefly, the antimiR constructs contained in the miRZip vectors were excised and ligated into pZacf-U6-luc-ZsGreen. Serotype 9 AAVs were packaged by transfection of 293T cells with the appropriate plasmids.

Organotypic Heart Slice Culture. Mice ventricles were washed in cold Modified Tyrode's Solution, embedded in 4% low melting point agarose and immediately cut into 300 μm slices using a vibratome (Leica). Heart slices were then maintained in complete IMDM 5%, 1% Pent/Strep in 12-well plates at the medium-air interface using 0.4 μm membrane transwells (Corning) at 37 C in a 5% CO₂ incubator. For experimental hypoxia-like conditions, slices were kept in a hypoxia chamber incubator for 4 hours at 37 C, 5% O₂. Lentiviral transduction was performed by immersion of the slices in virus-containing medium for 24 h.

Myocardial Infarction. Myocardial infarction was induced CD1 mice (8-12 weeks old) by permanent left anterior descending (LAD) coronary artery ligation. Briefly, mice were anesthetized with an injection of ketamine and xylazine, intubated and placed on a rodent ventilator. Body temperature was maintained at 37° C. on a heating pad. After removing the pericardium, a descending branch of the LAD coronary artery was visualized with a stereomicroscope and occluded with a nylon suture. Ligation was confirmed by the whitening of a region of the left ventricle. Recombinant AAV vectors, at a dose of 10¹¹ viral genome particles per animal, were injected immediately after LAD ligation into the myocardium bordering the infarct zone (single injection), using an insulin syringe with incorporated 30-gauge needle. Three groups of animals were studied, receiving AAV9-control (shRNA-Luc), AAV9-antimiR-99/100 or AAV9-anti-Let-7a/c. The chest was closed, and the animals moved to a prone position until the occurrence of spontaneous breathing. BrdU was administered intraperitoneally (500 μg per animal) every 2 days, for a period of ten days. Echocardiography analysis was performed at days 12, 30 and 60 after infarction, as described below, and hearts were collected at 12 (n=6 animals per group) and 60 (n=10 animals per group) days after infarction.

Echocardiography Analysis. To evaluate left ventricular function and dimensions, transthoracic two-dimensional echocardiography was performed on mice sedated with 5% isoflurane at 12, 30 and 60 days after myocardial infarction, using a Visual Sonics Vevo 770 Ultrasound (Visual Sonics) equipped with a 30-MHz linear array transducer. M-mode tracings in parasternal short axis view were used to measure left ventricular anterior and posterior wall thickness and left ventricular internal diameter at end-systole and end-diastole, which were used to calculate left ventricular fractional shortening and ejection fraction.

Heart Collection and Histological Analysis. At the end of the studies, animals were anaesthetized with 5% isoflurane and then killed by injection of 10% KCl, to stop the heart at diastole. The heart was excised, briefly washed in PBS, weighted, fixed in 10% formalin at room temperature, embedded in paraffin and further processed for histology or immunofluorescence. Haematoxylin-eosin and Masson's trichrome staining were performed according to standard procedures, and analysed for regular morphology and extent of fibrosis. Infarct size was measured as the percentage of the total left ventricular area showing fibrosis.

Zebrafish Heart Amputation. Adult fish were anaesthetized in 0.4% Tricaine and secured, ventral side uppermost, in a slotted sponge. Watchmaker forceps were used to remove the surface scales and penetrate the skin, muscle and pericardial sac. Once exposed, the ventricle was gently pulled at the apex and cut with iridectomy scissors. After surgery, fish were immediately returned to system water.

Cryosectioning. At the specified time points, hearts were removed, washed in PBS-EDTA 0.4% and fixed for 20 min in 4% paraformaldehyde at 4° C. Afterwards, they were washed several times in PBS, equilibrated in 30% sucrose, and then frozen for cryosectioning. 10 μm slices were obtained with a cryostat (Leica).

Real Time RT-PCR. For RNA, tissue was obtained from adult heart ventricles from different time points and conditions, extensively washed in PBS-EDTA 0.4% to remove blood, and then mechanically homogenized and processed using RNeasy kit (Qiagen) as per manufacturer's instructions. RT and PCR were performed using Quantitect Reverse Transcription Kit (Qiagen) and Quantitect Primers for the following genes: Fntb, Fntα, Smarca5, myc-a, myc-b, H-rasa, H-rasb, N-ras, K-ras, tnnt2. For miRNAs, small RNA (<200 pb) was obtained employing the miRNeasy mini kit (Qiagen) using the same procedure as before. RT and PCR reactions were carried out employing miRCURY LNA RT and PCR kits (Exiqon) and stem-loop LNA primers (Exiqon).

MicroRNA microarrays. RNA was obtained as for PCR applications. GenechipmiRNA 2.0 microarrays were purchased from Affymetrix and small RNA labeling was performed using FlashTag HSR labeling kit (Genesphere). 200 ng of small RNA was polyA-tailed and biotin conjugated. After labelling, RNA was hybridized using GeneChip reagents (Affymetrix) and protocols as indicated by the manufacturer. The chip contains hybridization probes for the miRbase v15 annotations, including 248 zebrafishmiRNAs. MicroRNA data was analyzed by using the R package.

Bioinformatic Analysis of miRNA Targets. Signaling pathways and downstream target prediction related to the identified miRNAs were determined by using DIANA, Miranda and TargetScan. Gene ontology analysis was performed with DAVID software.

Fluorescence In Situ Hybridization. 10 μm heart slices were further fixed in 4% PFA for 10 min at room temperature, washed in PBS and acetylated for 10 min in acetylation solution. After washing in PBS, samples were treated with proteinase K, prehybridized for 4 h and hybridized overnight at the appropriate temperature with LNA DIG-labeled probes for the corresponding miRNAs (Exiqon). The next day slides were washed and immunolabeled with anti-DIG-alkaline phosphatase antibodies (1:2,000) and antibodies against cardiomyocytic proteins of interest (1:100) overnight at 4° C. Secondary antibody incubation was performed as for immunofluorescence experiments. Alkaline phosphatase activity was detected by incubating samples in a Fast Red solution (Dako) for 2 hours. Samples were then washed, mounted in Vecta-shield and imaged in a confocal microscope. Fast Red fluorescence was detected with Cy3 settings.

Immunofluorescence. Tissue slices were fixed for 15 min in 4% paraformaldehyde, washed in PBS-gly 0.3 M, and blocked in PBS-10% donkey serum, 0.5% TX-100, 0.5% BSA for 1 hour. Primary antibodies were diluted at the appropriate concentrations in PBS-1% donkey serum, 0.5% TX-100, 0.5% BSA and incubated overnight. After washing, slices were incubated overnight with secondary antibodies, washed and mounted in Vecta-shield. Antibodies employed are listed in table S3.

Cell Culture. COS7 cells were maintained in DMEM (high glucose) supplemented with 10% FBS, L-Glutamine and non-essential amino acids (Invitrogen). Human ES cells, H1 and H9 (WA1 and WA9, WiCell), were cultured in chemically defined hES/hiPS growth media, mTeSR1 on growth factor reduced matrigel (BD biosciences) coated plates. Briefly, 70-80% confluent hES/iPS cells were treated with dispase (Invitrogen) for 7 minutes at 37° C. and the colonies were dispersed to small clusters and lifted carefully using a 5 ml glass pipette, at a ratio of ˜1:4.

Culture and Isolation of Adult Mouse Ventricular Myocytes. Wild-type mice (C57B6/J) were sacrificed and hearts were quickly recovered and washed with ice-cold Ca²⁺-free ModifiedTyrode's Solution (MTS). Ventricles were dissected from the rest of the heart and subjected to enzymatic digestion (Liberase DH, Roche) for 10-15 min in a spinner flask at 37 C under continuous agitation. Afterwards cells were pelleted by short centrifugation, resuspended in KB solution and cardiomyocytes were left to sediment by gravity, thus greatly reducing the presence of other contaminating cell types. Calcium was restore to 1 mM in a step-wise fashion in three gradual steps and subsequently cardiomyocytes were centrifuged, resuspended in culture medium (IMDM 5%, 1% Pen/Strep, 0.1 ng/ml FGFb, 1 ng/ml TGF-β3) and seeded in laminin-coated tissue-culture plates. Cells were kept in culture for 1 week.

Differentiation of Human ES Cells to Immature Cardiomyocytes. Human ES cells grown on matrigel dots (BD biosciences) were carefully dissociated using dispase and were plated on low attachment plates in EB media (IMDM, 20% FBS, 2.25 nM L-Glutamine and non-essential aminoacids). After 6 days of suspension in culture, the EBs were seeded on gelatin-coated plates in EB media. Spontaneously beating EBs were manually picked and used for further analysis. For directed differentiation, human ES cells grown in mTeSR on matrigel coated plates were treated with 12 μM GSK3β inhibitor CHIR 99021 (Stemgent) in cardiomyocyte differentiation base media (RPMI 1640 supplemented with 125 μg/ml human holo-transferrin (Sigma-Aldrich)) for 24 hours, followed by 24 hour of rest in the base media. On day 3, the cells were treated with 5 μM WNT inhibitor, IWP4 (Stemgent) for 48 hours, followed by treatment with Cardiac differentiation base media supplemented with 20 μg/ml human Insulin (SAFC) until colonies started beating.

Lentiviral Constructs. Anti-miR constructs, miRZip-99/100 and miRZip-let7 (SBI), were used according to the manufacturer instructions. As respective controls, the anti-miRs were removed from the parent vector by digesting with BamHI and EcoRI, end filled and re-ligated. Lentiviruses were packaged by transfecting in 293T cells followed by spinfection in the respective mouse or human ES derived cardiomyocytes.

Luciferase Constructs and microRNA Binding Validation. 3′ UTR of human and zebrafish FNTB and SMARCA5 were amplified with the indicated primers using genomic DNA as a template and were cloned into PGL3 vector (Promega) at the XhoI site downstream of luciferase gene. COS7 cells (seeded at 3×10⁴ cells per well of a 12 well plate and grown for 24 hours) were transfected with 50 ng each of indicated luciferase reporter vectors, pRL TK (Renilla luciferase control vector, Promega) either in the presence or absence of 20 nM or 40 nM of double stranded DNA oligonucleotide mimics of miR-99 or miR-100 (Dharmacon) using Lipofectamine (Invitrogen) following manufacturer's protocol. 12-16 hours post-transfection, cells were lysed using passive lysis buffer (Promega). Luminescent signals arising from the cell lysates obtained 12 hours post transfection of COS7 cells with appropriate luciferase constructs were measured using the Dual Luciferase assay system (Promega) in a Synergy H1 hybrid reader (BioTek). The relative luminescence intensity of each sample was calculated after normalization with corresponding Renilla luciferase activity, and were represented as % values compared to the corresponding sample without the miR mimic.

Confocal Microscopy. Samples were imaged using a Zeiss L710 confocal microscope. For every sample, at least two different fields were examined at two different magnifications (using a 20× objective and a 63× oil-immersion objective). Z-stacks were obtained for further analysis and 3D reconstruction. For intensity comparison purposes, images were taken with the same settings (pinhole size, laser intensity, etc).

Organotypic Heart Slice Culture. Mice ventricles were washed in cold Modified Tyrode's Solution, embedded in 4% low melting point agarose and immediately cut into 300 μm slices using a vibratome (Leica). Heart slices were then maintained in complete IMDM 5%, 1% Pent/Strep in 12-well plates at the medium-air interface using 0.4 μm membrane transwells (Corning) at 37 C in a 5% CO₂ incubator. For experimental hypoxia-like conditions, slices were kept in a hypoxia chamber incubator for 4 hours at 37 C, 5% O₂. Lentiviral transduction was performed by immersion of the slices in virus-containing medium for 24 h.

Morpholino and microRNA Injections in Zebrafish Embryos. Morpholinos (Gene Tools) were dissolved in water at a 2 mM stock concentration and diluted to a 2 ng/nl working concentration in PBS/phenol red solution. Embryo injections were performed by injecting ˜1 nl morpholino solution at the 1-cell stage using a FemtoJet (Eppendorf). For microRNA mimic injection, a miR-99/100 equimolar mixture at 2 ng/nl in PBS was employed. Morphants were evaluated at 24, 48 and 72 h in a StereoLumar stereoscope (Zeiss).

In Vivo microRNA Delivery. MicroRNA siRNA mimics without chemical modifications were purchased from Life Technologies, dissolved in nuclease-free water and complexed to jetPEI (10 N/P ratio) for in vivo, intra-cardiac administration. 0.2 μg siRNA was injected per animal every 2 days. To determine the efficiency of the delivery, a control Cy5-labeled siRNA directed against GFP was used in cmlc2:GFP animals. MicroRNA inhibitors against the miR-99/100 family were purchased from Exiqon and used at 0.2 μg siRNA per animal every 2 days.

Tipifarnib Injections. Tipifarnib was dissolved in DMSO at 10 mg/ml and 2 μl were administered by intraperitoneal injection (final concentration 0.02 mg/animal) every 2 days for 14 days. Control animals were administered DMSO.

BrdU Labeling. Fish were anaesthetized in 0.4% Tricaine, and 10 μl of a 10 mg/ml solution of BrdU (in PBS) was injected into the abdominal cavity once every 2 days for 14 days. At that point, hearts were removed and fixed overnight in 4% paraformaldehyde at 4° C., washed in PBS, equilibrated in 30% sucrose in PBS and frozen for cryosectioning.

Histology and Histomorphometry. Masson's trichrome staining was performed in 10 μm tissue slices by immersion in Bouin's fixative followed by sequential incubation in Weigert's hematoxylin, Acid Fuchsin, phosphotungstic/phosphomolybdic acid, Aniline Blue and acetic acid. After washes, slices were mounted for bright field observation. Histomorphometric measurements were performed with Fiji. Injured areas were quantified in four independent different slices per animal (four animals were used per condition) and normalized to whole tissue area.

Statistical Analysis. Results are expressed as mean±SEM. Statistical significance was determined by Student's t-test. Results are representative of at least 3 independent experiments except when otherwise indicated.

TABLE S1 miR-99/100 predicted targets SEQ Total Target Representative ID Representative context + Aggregate Publication gene transcript NO: Gene name miRNA score PCT (s) FGFR3 NM_000142 1 fibroblast growth hsa-miR-99a −0.47 <0.1 2005, factor receptor 3 2007, 2009 IGF1R NM_000875 2 insulin-like growth hsa-miR-100 −0.26 <0.1 2007, factor 1 receptor 2009 PPP3CA NM_000944 3 protein phosphatase hsa-miR-99a −0.26 <0.1 2009 3, catalytic subunit, alpha isozyme ZNF197 NM_001024855 4 zinc finger protein hsa-miR-100 −0.65 <0.1 197 TTC39A NM_001080494 5 tetratricopeptide hsa-miR-99a −0.55 <0.1 2007, repeat domain 39A 2009 NXF1 NM_001081491 6 nuclear RNA export hsa-miR-100 −0.2 0.11 2009 factor 1 SMARCA4 NM_001128844 7 SWI/SNF related, hsa-miR-100 −0.26 0.11 matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 LRRC8B NM_001134476 8 leucine rich repeat hsa-miR-99a −0.29 <0.1 containing 8 family, member B EIF2C2 NM_001164623 9 eukaryotic translation hsa-miR-100 −0.4 <0.1 2005, initiation factor 2C, 2 2007, 2009 TMEM135 NM_001168724 10 transmembrane hsa-miR-100 −0.28 0.11 protein 135 CLDN11 NM_001185056 11 claudin 11 hsa-miR-100 −0.29 <0.1 2009 BMPR2 NM_001204 12 bone morphogenetic hsa-miR-100 −0.28 0.11 2005, protein receptor, type 2007, II (serine/threonine 2009 kinase) INSM1 NM_002196 13 insulinoma- hsa-miR-99a −0.25 <0.1 2005, associated 1 2007 PPP1CB NM_002709 14 protein phosphatase hsa-miR-100 −0.31 0.11 2009 1, catalytic subunit, beta isozyme FZD5 NM_003468 15 frizzled family hsa-miR-100 −0.3 <0.1 2007, receptor 5 2009 SMARCA5 NM_003601 16 SWI/SNF related, hsa-miR-100 −0.45 <0.1 2005, matrix associated, 2007, actin dependent 2009 regulator of chromatin, subfamily a, member 5 PPFIA3 NM_003660 17 protein tyrosine hsa-miR-100 −0.3 0.11 2005, phosphatase, receptor 2007, type, f polypeptide 2009 (PTPRF), interacting protein (liprin), alpha 3 MTOR NM_004958 18 mechanistic target of hsa-miR-100 −0.38 <0.1 2005, rapamycin 2007, (serine/threonine 2009 kinase) ST5 NM_005418 19 suppression of hsa-miR-100 −0.33 <0.1 tumorigenicity 5 HOXA1 NM_005522 20 homeobox A1 hsa-miR-99a −0.33 <0.1 2005, 2007, 2009 HS3ST3B1 NM_006041 21 heparan sulfate hsa-miR-99a −0.59 <0.1 2005, (glucosamine) 3-O- 2007, sulfotransferase 3B1 2009 HS3ST2 NM_006043 22 heparan sulfate hsa-miR-100 −0.6 <0.1 2005, (glucosamine) 3-O- 2007, sulfotransferase 2 2009 ICMT NM_012405 23 isoprenylcysteine hsa-miR-99a −0.15 <0.1 2005, carboxyl 2007, methyltransferase 2009 BAZ2A NM_013449 24 bromodomain hsa-miR-100 −0.46 <0.1 2005, adjacent to zinc 2007, finger domain, 2A 2009 ZZEF1 NM_015113 25 zinc finger, ZZ-type hsa-miR-100 −0.42 <0.1 2005, with EF-hand 2007, domain 1 2009 NIPBL NM_015384 26 Nipped-B homolog hsa-miR-99a −0.3 0.11 (Drosophila) PI15 NM_015886 27 peptidase inhibitor hsa-miR-99a −0.19 0.11 2009 15 ZBTB7A NM_015898 28 zinc finger and BTB hsa-miR-100 −0.16 0.11 2007, domain containing 2009 7A PPPDE1 NM_016076 29 PPPDE peptidase hsa-miR-99a −0.26 0.11 2009 domain containing 1 EPDR1 NM_017549 30 ependymin related hsa-miR-100 −0.69 <0.1 2009 protein 1 (zebrafish) RAVER2 NM_018211 31 ribonucleoprotein, hsa-miR-99a −0.44 <0.1 2007, PTB-binding 2 2009 CYP26B1 NM_019885 32 cytochrome P450, hsa-miR-100 −0.14 <0.1 2005, family 26, subfamily 2007, B, polypeptide 1 2009 TAOK1 NM_020791 33 TAO kinase 1 hsa-miR-100 −0.21 <0.1 MBNL1 NM_021038 34 muscleblind-like hsa-miR-99a −0.2 <0.1 2005, (Drosophila) 2007, 2009 MTMR3 NM_021090 35 myotubularin related hsa-miR-99a −0.18 <0.1 2005, protein 3 2007, 2009 ADCY1 NM_021116 36 adenylate cyclase 1 hsa-miR-99a −0.4 <0.1 2005, (brain) 2007, 2009 RRAGD NM_021244 37 Ras-related GTP hsa-miR-100 −0.35 <0.1 binding D TRIB2 NM_021643 38 tribbles homolog 2 hsa-miR-100 −0.31 <0.1 2005, (Drosophila) 2007, 2009 CEP85 NM_022778 39 centrosomal protein hsa-miR-99a −0.29 0.11 2007, 85 kDa 2009 RMND5A NM_022780 40 required for meiotic hsa-miR-99a −0.15 0.11 nuclear division 5 homolog A (S. cerevisiae) THAP2 NM_031435 41 THAP domain hsa-miR-100 −0.64 0.11 2007, containing, apoptosis 2009 associated protein 2 FZD8 NM_031866 42 frizzled family hsa-miR-100 −0.34 <0.1 2005, receptor 8 2007, 2009 KBTBD8 NM_032505 43 kelch repeat and hsa-miR-100 −0.6 <0.1 2007, BTB (POZ) domain 2009 containing 8 SLC44A1 NM_080546 44 solute carrier family hsa-miR-100 −0.31 <0.1 2007, 44, member 1 2009 ZNRF2 NM_147128 45 zinc and ring finger 2 hsa-miR-100 −0.24 0.11 ST6GALNAC4 NM_175039 46 ST6 (alpha-N-acetyl- hsa-miR-99a −0.56 <0.1 neuraminyl-2,3-beta- galactosyl-1,3)-N- acetylgalactosaminide alpha-2,6- sialyltransferase 4 GRHL1 NM_198182 47 grainyhead-like 1 hsa-miR-99a −0.3 0.11 2009 (Drosophila)

TABLE S2 Let-7a/c predicted targets. SEQ Total Target Representative ID Representative context + Aggregate Publication gene transcript NO: Gene name miRNA score PCT (s) ADRB2 NM_000024 48 adrenergic, beta-2-, hsa-miR- −0.47 0.63 2005, receptor, surface 4458 2007, 2009 ADRB3 NM_000025 49 adrenergic, beta-3-, hsa-miR- −0.28 0.98 2005, receptor 4458 2007, 2009 FAS NM_000043 50 Fas (TNF receptor hsa-miR-98 −0.32 0.85 2009 superfamily, member 6) ATP7B NM_000053 51 ATPase, Cu++ hsa-miR- −0.09 0.93 2009 transporting, beta 4458 polypeptide CAPN3 NM_000070 52 calpain 3, (p94) hsa-miR- −0.15 0.92 2009 4458 CLCN5 NM_000084 53 chloride channel 5 hsa-let-7c −0.4 >0.99 2007, 2009 COL1A1 NM_000088 54 collagen, type I, alpha 1 hsa-miR- −0.18 0.89 2005, 4500 2007, 2009 COL1A2 NM_000089 55 collagen, type I, alpha 2 hsa-miR- −0.41 0.95 2005, 4500 2007, 2009 COL3A1 NM_000090 56 collagen, type III, hsa-miR- −0.37 0.92 2005, alpha 1 4458 2007, 2009 CYP19A1 NM_000103 57 cytochrome P450, hsa-let-7f −0.22 0.9 2005, family 19, subfamily 2007, A, polypeptide 1 2009 DMD NM_000109 58 dystrophin hsa-let-7d −0.29 0.84 2005, 2007, 2009 ERCC6 NM_000124 59 excision repair cross- hsa-let-7d −0.46 0.95 2005, complementing 2007, rodent repair 2009 deficiency, complementation group 6 GALC NM_000153 60 galactosylceramidase hsa-miR- −0.27 0.93 2009 4458 GHR NM_000163 61 growth hormone hsa-miR-98 −0.16 0.87 2005, receptor 2007, 2009 HK2 NM_000189 62 hexokinase 2 hsa-miR- −0.06 0.89 2005, 4500 2007, 2009 TBX5 NM_000192 63 T-box 5 hsa-miR- −0.16 0.94 2005, 4500 2007, 2009 INSR NM_000208 64 insulin receptor hsa-let-7i −0.11 0.99 2007, 2009 ITGB3 NM_000212 65 integrin, beta 3 hsa-miR- −0.21 >0.99 2005, (platelet glycoprotein 4458 2007, IIIa, antigen CD61) 2009 RB1 NM_000321 66 retinoblastoma 1 hsa-miR- −0.1 0.83 2005, 4500 2007, 2009 SCN5A NM_000335 67 sodium channel, hsa-miR- −0.04 0.95 2005, voltage-gated, type V, 4458 2007, alpha subunit 2009 SGCD NM_000337 68 sarcoglycan, delta hsa-miR- >−0.02 0.7 2005, (35 kDa dystrophin- 4458 2007, associated 2009 glycoprotein) TSC1 NM_000368 69 tuberous sclerosis 1 hsa-miR- −0.22 0.95 2005, 4458 2007, 2009 CDKN1A NM_000389 70 cyclin-dependent hsa-let-7i −0.24 0.76 2009 kinase inhibitor 1A (p21, Cip1) TPP1 NM_000391 71 tripeptidyl peptidase I hsa-miR- −0.24 0.97 2009 4458 COL5A2 NM_000393 72 collagen, type V, hsa-miR- −0.16 0.95 2005, alpha 2 4458 2007, 2009 GALE NM_000403 73 UDP-galactose-4- hsa-miR- −0.28 0.91 2005, epimerase 4458 2007, 2009 LOR NM_000427 74 loricrin hsa-let-7g −0.27 0.88 2009 RAG1 NM_000448 75 recombination hsa-let-7a −0.17 0.76 2009 activating gene 1 AMT NM_000481 76 aminomethyltransferase hsa-let-7a −0.29 0.82 2009 COL4A5 NM_000495 77 collagen, type IV, hsa-miR- −0.14 0.91 2005, alpha 5 4500 2007, 2009 KCNJ11 NM_000525 78 potassium inwardly- hsa-let-7d −0.44 0.78 2009 rectifying channel, subfamily J, member 11 TP53 NM_000546 79 tumor protein p53 hsa-let-7d −0.28 0.93 2009 DCX NM_000555 80 doublecortin hsa-let-7d −0.05 0.87 2005, 2007 IL6R NM_000565 81 interleukin 6 receptor hsa-miR- −0.16 0.94 4500 IL10 NM_000572 82 interleukin 10 hsa-let-7e −0.14 0.94 2005, 2007, 2009 IL6 NM_000600 83 interleukin 6 hsa-miR- −0.15 0.73 2007 (interferon, beta 2) 4500 IGF1 NM_000618 84 insulin-like growth hsa-let-7f −0.1 0.97 2009 factor 1 (somatomedin C) NOS1 NM_000620 85 nitric oxide synthase hsa-miR- −0.11 0.95 1 (neuronal) 4458 FASLG NM_000639 86 Fas ligand (TNF hsa-miR- −0.26 0.98 2005, superfamily, member 4458 2007, 6) 2009 ADRB1 NM_000684 87 adrenergic, beta-1-, hsa-miR- −0.25 0.98 2007, receptor 4500 2009 CACNA1D NM_000720 88 calcium channel, hsa-let-7b −0.07 0.88 2005, voltage-dependent, L 2007, type, alpha 1D 2009 subunit CACNA1E NM_000721 89 calcium channel, hsa-miR- −0.01 0.93 2005, voltage-dependent, R 4500 2007, type, alpha 1E subunit 2009 GABRA6 NM_000811 90 gamma-aminobutyric hsa-let-7d −0.16 0.84 2009 acid (GABA) A receptor, alpha 6 HTR1E NM_000865 91 5-hydroxytryptamine hsa-let-7d −0.27 0.89 2009 (serotonin) receptor 1E HTR4 NM_000870 92 5-hydroxytryptamine hsa-let-7a −0.12 0.94 2005, (serotonin) receptor 4 2007, 2009 IGF1R NM_000875 93 insulin-like growth hsa-let-7b −0.42 >0.99 2007, factor 1 receptor 2009 OPRM1 NM_000914 94 opioid receptor, mu 1 hsa-miR- −0.2 0.92 2005, 4500 2007, 2009 PTAFR NM_000952 95 platelet-activating hsa-miR- −0.69 0.94 factor receptor 4500 NKIRAS2 NM_001001349 96 NFKB inhibitor hsa-miR- −0.09 0.88 2005, interacting Ras-like 2 4458 2007, 2009 ATP2B4 NM_001001396 97 ATPase, Ca++ hsa-let-7f −0.05 0.93 2005, transporting, plasma 2007, membrane 4 2009 RORC NM_001001523 98 RAR-related orphan hsa-miR- −0.12 0.93 2005, receptor C 4458 2007, 2009 GDF6 NM_001001557 99 growth differentiation hsa-miR- −0.5 0.98 2005, factor 6 4500 2007, 2009 MTUS1 NM_001001924 100 microtubule hsa-let-7d −0.14 0.71 2009 associated tumor suppressor 1 PPARA NM_001001928 101 peroxisome hsa-miR- −0.04 0.97 2007, proliferator-activated 4458 2009 receptor alpha GOLGA7 NM_001002296 102 golgin A7 hsa-miR- −0.15 0.7 2005, 4500 2007, 2009 WNK3 NM_001002838 103 WNK lysine deficient hsa-miR- −0.09 0.91 protein kinase 3 4458 CACNA1I NM_001003406 104 calcium channel, hsa-miR- −0.1 0.92 2009 voltage-dependent, T 4458 type, alpha 1I subunit SMAD2 NM_001003652 105 SMAD family hsa-miR- −0.09 0.9 2007, member 2 4458 2009 C18orf1 NM_001003674 106 chromosome 18 open hsa-miR- −0.01 0.76 reading frame 1 4500 KLHL31 NM_001003760 107 kelch-like 31 hsa-let-7d −0.34 0.93 2009 (Drosophila) MGLL NM_001003794 108 monoglyceride lipase hsa-miR- >−0.03 0.99 2005, 4458 2007, 2009 DLGAP1 NM_001003809 109 discs, large hsa-miR- −0.03 0.81 (Drosophila) 4500 homolog-associated protein 1 CD200 NM_001004196 110 CD200 molecule hsa-miR-98 −0.12 0.75 ZNF740 NM_001004304 111 zinc finger protein hsa-let-7d >−0.02 0.94 2007, 740 2009 LIN28B NM_001004317 112 lin-28 homolog B (C. elegans) hsa-let-7d −0.98 >0.99 2007, 2009 PLEKHG7 NM_001004330 113 pleckstrin homology hsa-miR- −0.34 0.94 2009 domain containing, 4458 family G (with RhoGef domain) member 7 TRIM67 NM_001004342 114 tripartite motif hsa-let-7f −0.08 >0.99 2007, containing 67 2009 NRARP NM_001004354 115 NOTCH-regulated hsa-miR- −0.2 0.67 2005, ankyrin repeat protein 4458 2007, 2009 ITGA11 NM_001004439 116 integrin, alpha 11 hsa-miR- −0.07 0.77 4458 YPEL2 NM_001005404 117 yippee-like 2 hsa-miR- −0.15 0.96 2009 (Drosophila) 4500 PLCXD3 NM_001005473 118 phosphatidylinositol- hsa-miR- −0.19 0.8 2005, specific 4458 2007 phospholipase C, X domain containing 3 CPM NM_001005502 119 carboxypeptidase M hsa-miR- −0.27 0.95 2005, 4458 2007, 2009 EDA NM_001005609 120 ectodysplasin A hsa-miR- −0.06 0.92 2005, 4458 2007, 2009 ZNF473 NM_001006656 121 zinc finger protein hsa-let-7d −0.31 0.98 2009 473 NTRK3 NM_001007156 122 neurotrophic tyrosine hsa-let-7f −0.16 0.82 2009 kinase, receptor, type 3 IGF2BP2 NM_001007225 123 insulin-like growth hsa-let-7b −0.4 >0.99 2007, factor 2 mRNA 2009 binding protein 2 BRWD1 NM_001007246 124 bromodomain and hsa-let-7d −0.5 0.73 WD repeat domain containing 1 PRDM2 NM_001007257 125 PR domain containing hsa-let-7g −0.35 0.87 2, with ZNF domain GEMIN7 NM_001007269 126 gem (nuclear hsa-miR- −0.37 <0.1 2009 organelle) associated 4500 protein 7 IRGQ NM_001007561 127 immunity-related hsa-let-7g −0.11 0.85 GTPase family, Q BCAP29 NM_001008405 128 B-cell receptor- hsa-miR- −0.16 0.94 2007, associated protein 29 4500 2009 STEAP3 NM_001008410 129 STEAP family hsa-miR- −0.28 0.98 2009 member 3 4458 KIAA2022 NM_001008537 130 KIAA2022 hsa-let-7g −0.12 0.92 2009 USP20 NM_001008563 131 ubiquitin specific hsa-miR- −0.06 0.84 peptidase 20 4500 FNIP1 NM_001008738 132 folliculin interacting hsa-miR-98 −0.22 0.98 2007, protein 1 2009 ACSL6 NM_001009185 133 acyl-CoA synthetase hsa-let-7d −0.39 0.98 2005, long-chain family 2007, member 6 2009 MFAP3L NM_001009554 134 microfibrillar- hsa-miR- −0.09 0.93 2009 associated protein 3- 4500 like MEIS3 NM_001009813 135 Meis homeobox 3 hsa-miR- −0.26 0.92 2005, 4458 2007, 2009 KIAA0930 NM_001009880 136 KIAA0930 hsa-let-7d −0.06 >0.99 2007, 2009 C20orf194 NM_001009984 137 chromosome 20 open hsa-miR- −0.18 >0.99 2009 reading frame 194 4500 ARHGAP28 NM_001010000 138 Rho GTPase hsa-let-7a −0.35 0.95 2005, activating protein 28 2007, 2009 PM20D2 NM_001010853 139 peptidase M20 hsa-let-7a −0.19 0.78 domain containing 2 ACER2 NM_001010887 140 alkaline ceramidase 2 hsa-miR- −0.15 0.94 2007, 4458 2009 SLC5A9 NM_001011547 141 solute carrier family 5 hsa-miR- −0.5 0.79 2009 (sodium/glucose 4458 cotransporter), member 9 NAA30 NM_001011713 142 N(alpha)- hsa-miR- −0.16 0.94 2007, acetyltransferase 30, 4500 2009 NatC catalytic subunit NHLRC3 NM_001012754 143 NHL repeat hsa-let-7a −0.27 0.95 2007, containing 3 2009 SNX30 NM_001012994 144 sorting nexin family hsa-let-7d −0.15 0.95 2009 member 30 FIGNL2 NM_001013690 145 fidgetin-like 2 hsa-miR- −1.07 >0.99 2009 4458 C8orf58 NM_001013842 146 chromosome 8 open hsa-let-7d −0.42 0.97 2009 reading frame 58 DCUN1D2 NM_001014283 147 DCN1, defective in hsa-let-7b −0.13 0.94 2007, cullin neddylation 1, 2009 domain containing 2 (S. cerevisiae) KATNAL1 NM_001014380 148 katanin p60 subunit hsa-miR- −0.28 0.94 2009 A-like 1 4458 USP21 NM_001014443 149 ubiquitin specific hsa-miR- −0.12 0.92 2005, peptidase 21 4458 2007, 2009 DDX19B NM_001014449 150 DEAD (Asp-Glu-Ala- hsa-miR- −0.47 0.97 2007, As) box polypeptide 4500 2009 19B RTKN NM_001015055 151 rhotekin hsa-miR-98 −0.14 0.76 GOPC NM_001017408 152 golgi-associated PDZ hsa-miR- −0.1 0.87 2009 and coiled-coil motif 4500 containing CALN1 NM_001017440 153 calneuron 1 hsa-miR- −0.15 0.92 2009 4458 C14orf28 NM_001017923 154 chromosome 14 open hsa-let-7g −1.25 >0.99 2007, reading frame 28 2009 OPA3 NM_001017989 155 optic atrophy 3 hsa-miR- −0.42 0.71 (autosomal recessive, 4458 with chorea and spastic paraplegia) DKK3 NM_001018057 156 dickkopf homolog 3 hsa-let-7d −0.1 0.93 2007, (Xenopus laevis) 2009 SERF2 NM_001018108 157 small EDRK-rich hsa-let-7d −0.55 0.85 factor 2 IQCB1 NM_001023570 158 IQ motif containing hsa-miR- −0.3 0.88 2009 B1 4500 SBK1 NM_001024401 159 SH3-binding domain hsa-let-7b −0.1 0.94 2007, kinase 1 2009 CD276 NM_001024736 160 CD276 molecule hsa-miR- −0.06 0.71 4458 BCL7A NM_001024808 161 B-cell hsa-miR- −0.06 0.9 2005, CLL/lymphoma 7A 4500 2007, 2009 KCTD21 NM_001029859 162 potassium channel hsa-miR-98 −0.54 0.98 2007, tetramerisation 2009 domain containing 21 SLC10A7 NM_001029998 163 solute carrier family hsa-miR-98 −0.25 0.94 10 (sodium/bile acid cotransporter family), member 7 CTNS NM_001031681 164 cystinosin, lysosomal hsa-let-7d −0.12 0.93 2005, cystine transporter 2007, 2009 RBFOX2 NM_001031695 165 RNA binding protein, hsa-miR-98 −0.19 0.94 2005, fox-1 homolog (C. elegans) 2 2007, 2009 PLD3 NM_001031696 166 phospholipase D hsa-miR- −0.13 0.9 2005, family, member 3 4458 2007, 2009 ERGIC1 NM_001031711 167 endoplasmic hsa-let-7d −0.21 0.93 reticulum-golgi intermediate compartment (ERGIC) 1 TMPO NM_001032283 168 thymopoietin hsa-miR- −0.1 0.83 4500 STK24 NM_001032296 169 serine/threonine hsa-miR- −0.11 0.93 2009 kinase 24 4458 MYCL1 NM_001033081 170 v-myc hsa-let-7a −0.09 0.88 2007, myelocytomatosis 2009 viral oncogene homolog 1, lung carcinoma derived (avian) SRGAP3 NM_001033117 171 SLIT-ROBO Rho hsa-miR- −0.13 0.94 2005, GTPase activating 4500 2007, protein 3 2009 WIPI2 NM_001033518 172 WD repeat domain, hsa-let-7e −0.34 0.92 2009 phosphoinositide interacting 2 RRM2 NM_001034 173 ribonucleotide hsa-miR- −0.36 0.95 2007, reductase M2 4500 2009 ARL5A NM_001037174 174 ADP-ribosylation hsa-let-7g −0.13 0.94 2007, factor-like 5A 2009 CDC42SE1 NM_001038707 175 CDC42 small effector 1 hsa-miR- −0.22 0.71 2009 4500 TRIM71 NM_001039111 176 tripartite motif hsa-miR- −0.89 >0.99 2007, containing 71 4458 2009 TRIOBP NM_001039141 177 TRIO and F-actin hsa-miR- −0.12 0.86 2009 binding protein 4458 GK5 NM_001039547 178 glycerol kinase 5 hsa-let-7d −0.16 0.85 (putative) KREMEN1 NM_001039570 179 kringle containing hsa-miR- −0.17 0.97 2007, transmembrane 4458 2009 protein 1 SEC14L1 NM_001039573 180 SEC14-like 1 (S. cerevisiae) hsa-miR- −0.18 0.92 2005, 4500 2007, 2009 KCNC4 NM_001039574 181 potassium voltage- hsa-miR- −0.1 0.84 2009 gated channel, Shaw- 4500 related subfamily, member 4 TMPPE NM_001039770 182 transmembrane hsa-miR- −0.17 0.84 2009 protein with 4458 metallophosphoesterase domain CHIC1 NM_001039840 183 cysteine-rich hsa-miR- >−0.04 >0.99 2009 hydrophobic domain 1 4458 MLLT4 NM_001040000 184 myeloid/lymphoid or hsa-miR- −0.16 0.74 2007, mixed-lineage 4458 2009 leukemia (trithorax homolog, Drosophila); translocated to, 4 PQLC2 NM_001040125 185 PQ loop repeat hsa-miR- −0.3 0.95 2009 containing 2 4458 PEG10 NM_001040152 186 paternally expressed hsa-miR- −0.02 0.71 2009 10 4458 MTMR12 NM_001040446 187 myotubularin related hsa-miR- −0.06 0.9 2009 protein 12 4458 PTPRD NM_001040712 188 protein tyrosine hsa-miR- −0.22 0.96 2007, phosphatase, receptor 4500 2009 type, D KIAA0895L NM_001040715 189 KIAA0895-like hsa-let-7i −0.14 0.93 2007, 2009 USP44 NM_001042403 190 ubiquitin specific hsa-miR- −0.14 0.93 2009 peptidase 44 4458 RUFY2 NM_001042417 191 RUN and FYVE hsa-miR-98 −0.27 0.82 domain containing 2 C6orf204 NM_001042475 192 chromosome 6 open hsa-miR- −0.13 0.94 reading frame 204 4458 DLGAP4 NM_001042486 193 discs, large hsa-let-7d −0.31 0.97 2009 (Drosophila) homolog-associated protein 4 C2orf88 NM_001042519 194 chromosome 2 open hsa-miR- −0.17 0.89 2009 reading frame 88 4500 ATPAF1 NM_001042546 195 ATP synthase hsa-let-7d −0.43 0.92 2009 mitochondrial F1 complex assembly factor 1 FRS2 NM_001042555 196 fibroblast growth hsa-let-7i −0.04 0.86 2007, factor receptor 2009 substrate 2 EIF4G2 NM_001042559 197 eukaryotic translation hsa-let-7d −0.27 0.92 2005, initiation factor 4 2007, gamma, 2 2009 DPH3 NM_001047434 198 DPH3, KTI11 hsa-let-7i −0.4 0.98 homolog (S. cerevisiae) UHRF1 NM_001048201 199 ubiquitin-like with hsa-let-7d −0.17 0.94 2009 PHD and ring finger domains 1 TNFRSF1B NM_001066 200 tumor necrosis factor hsa-miR- −0.09 0.99 2005, receptor superfamily, 4458 2007, member 1B 2009 CDC14B NM_001077181 201 CDC14 cell division hsa-miR- −0.08 0.88 2009 cycle 14 homolog B 4500 (S. cerevisiae) ATG9A NM_001077198 202 ATG9 autophagy hsa-let-7d −0.03 0.74 related 9 homolog A (S. cerevisiae) SREK1 NM_001077199 203 splicing regulatory hsa-miR- −0.09 0.92 2005, glutamine/lysine-rich 4458 2007, protein 1 2009 IKZF2 NM_001079526 204 IKAROS family zinc hsa-let-7g −0.13 0.98 2007, finger 2 (Helios) 2009 CPEB1 NM_001079533 205 cytoplasmic hsa-miR- −0.44 0.91 2007, polyadenylation 4500 2009 element binding protein 1 FNDC3A NM_001079673 206 fibronectin type III hsa-let-7d −0.39 0.97 2005, domain containing 3A 2007, 2009 GYG2 NM_001079855 207 glycogenin 2 hsa-let-7a −0.22 0.88 2009 VAV3 NM_001079874 208 vav 3 guanine hsa-miR- −0.11 0.92 2005, nucleotide exchange 4500 2007, factor 2009 DMP1 NM_001079911 209 dentin matrix acidic hsa-miR- −0.21 0.94 2005, phosphoprotein 1 4500 2007, 2009 LDB3 NM_001080114 210 LIM domain binding 3 hsa-miR- −0.09 0.84 2009 4458 GJC1 NM_001080383 211 gap junction protein, hsa-miR- −0.42 0.95 2009 gamma 1, 45 kDa 4500 KIAA1147 NM_001080392 212 KIAA1147 hsa-miR- −0.15 0.86 2007, 4458 2009 SLC45A4 NM_001080431 213 solute carrier family hsa-let-7d −0.08 0.91 2003, 45, member 4 2007, 2009 DNA2 NM_001080449 214 DNA replication hsa-miR- −0.53 0.6 2009 helicase 2 homolog 4458 (yeast) MYO5B NM_001080467 215 myosin VB hsa-let-7g −0.04 0.78 2009 ZNF697 NM_001080470 216 zinc finger protein hsa-miR- −0.14 0.93 2007, 697 4458 2009 ZNF275 NM_001080485 217 zinc finger protein hsa-miR- −0.11 0.99 2007, 275 4458 2009 MGA NM_001080541 218 MAX gene associated hsa-miR- −0.12 0.91 2007, 4500 2009 THOC2 NM_001081550 219 THO complex 2 hsa-miR- −0.17 0.85 2007, 4458 2009 CPSF4 NM_001081559 220 cleavage and hsa-miR- −0.12 0.77 2005, polyadenylation 4458 2007, specific factor 4, 2009 30 kDa C11orf57 NM_001082969 221 chromosome 11 open hsa-let-7f −0.25 0.89 2007, reading frame 57 2009 E2F5 NM_001083588 222 E2F transcription hsa-miR- −0.3 0.86 2009 factor 5, p130-binding 4500 ANKRD12 NM_001083625 223 ankyrin repeat hsa-miR- >−0.02 0.77 domain 12 4458 FOXN3 NM_001085471 224 forkhead box N3 hsa-miR- >−0.01 0.82 4458 MEX3A NM_001093725 225 mex-3 homolog A (C. elegans) hsa-miR-98 −0.15 0.92 2009 HIC1 NM_001098202 226 hypermethylated in hsa-miR- −0.05 0.84 2009 cancer 1 4458 MGAT3 NM_001098270 227 mannosyl (beta-1,4-)- hsa-miR- >−0.02 0.66 glycoprotein beta-1,4- 4458 N- acetylglucosaminyltransferase SLC4A4 NM_001098484 228 solute carrier family hsa-miR- −0.16 0.95 2005, 4, sodium bicarbonate 4458 2007, cotransporter, 2009 member 4 FAM104A NM_001098832 229 family with sequence hsa-miR- −0.21 0.92 2007, similarity 104, 4458 2009 member A ATXN7L3 NM_001098833 230 ataxin 7-like 3 hsa-miR- −0.06 0.74 4500 BTBD9 NM_001099272 231 BTB (POZ) domain hsa-let-7a −0.16 0.95 2009 containing 9 NIPAL4 NM_001099287 232 NIPA-like domain hsa-miR- −0.17 0.93 2009 containing 4 4458 SH3RF3 NM_001099289 233 SH3 domain hsa-miR- −0.08 0.92 2009 containing ring finger 3 4458 GXYLT1 NM_001099650 234 glucoside hsa-miR- −0.37 0.99 2009 xylosyltransferase 1 4500 PTAR1 NM_001099666 235 protein hsa-miR- −0.15 0.98 2009 prenyltransferase 4500 alpha subunit repeat containing 1 FBXL19 NM_001099784 236 F-box and leucine- hsa-miR- −0.1 0.7 2009 rich repeat protein 19 4458 ACTA1 NM_001100 237 actin, alpha 1, skeletal hsa-let-7c −0.21 0.72 2005, muscle 2007 PHACTR2 NM_001100164 238 phosphatase and actin hsa-miR- −0.15 0.94 2009 regulator 2 4500 MOBKL3 NM_001100819 239 MOB1, Mps One hsa-let-7a −0.12 0.93 2005, Binder kinase 2007, activator-like 3 2009 (yeast) PACS2 NM_001100913 240 phosphofurin acidic hsa-miR- −0.14 0.79 2009 cluster sorting protein 2 4458 IGLON5 NM_001101372 241 IgLON family hsa-let-7d −0.04 0.94 2009 member 5 SAMD12 NM_001101676 242 sterile alpha motif hsa-miR- −0.05 0.94 2009 domain containing 12 4500 DTX2 NM_001102594 243 deltex homolog 2 hsa-let-7d −0.46 >0.99 2005, (Drosophila) 2007, 2009 FAM118A NM_001104595 244 family with sequence hsa-miR- −0.28 0.98 2007, similarity 118, 4500 2009 member A FAM123C NM_001105193 245 family with sequence hsa-miR- −0.25 0.87 2009 similarity 123C 4500 PCDH19 NM_001105243 246 protocadherin 19 hsa-miR- −0.12 0.95 2007, 4500 2009 ZFYVE16 NM_001105251 247 zinc finger, FYVE hsa-miR- −0.16 0.71 2009 domain containing 16 4500 SWT1 NM_001105518 248 SWT1 RNA hsa-let-7b −0.21 0.85 2007, endoribonuclease 2009 homolog (S. cerevisiae) CAP1 NM_001105530 249 CAP, adenylate hsa-miR- −0.14 0.85 2005, cyclase-associated 4500 2007, protein 1 (yeast) 2009 FAM135A NM_001105531 250 family with sequence hsa-let-7f −0.19 0.85 2005, similarity 135, 2007, member A 2009 ZBTB10 NM_001105539 251 zinc finger and BTB hsa-miR- −0.06 0.72 2005, domain containing 10 4500 2007 NEFM NM_001105541 252 neurofilament, hsa-let-7f −0.16 0.86 2007, medium polypeptide 2009 FBXO45 NM_001105573 253 F-box protein 45 hsa-miR- −0.06 0.89 2009 4458 ACVR2B NM_001106 254 activin A receptor, hsa-miR- −0.03 >0.99 2007, type IIB 4500 2009 C12orf51 NM_001109662 255 chromosome 12 open hsa-miR- −0.09 0.92 2009 reading frame 51 4458 GSG1L NM_001109763 256 GSG1-like hsa-miR- −0.08 0.73 4458 ACVR1C NM_001111031 257 activin A receptor, hsa-miR- −0.48 0.99 2005, type IC 4458 2007, 2009 C3orf63 NM_001112736 258 chromosome 3 open hsa-miR- −0.02 0.91 2009 reading frame 63 4458 HIPK2 NM_001113239 259 homeodomain hsa-let-7d −0.03 0.94 2009 interacting protein kinase 2 AMOT NM_001113490 260 angiomotin hsa-miR- −0.12 0.76 4458 ARHGEF7 NM_001113513 261 Rho guanine hsa-let-7a −0.14 0.94 nucleotide exchange factor (GEF) 7 CTSC NM_001114173 262 cathepsin C hsa-miR- −0.15 0.89 2009 4458 ADCY9 NM_001116 263 adenylate cyclase 9 hsa-miR- −0.03 0.91 2005, 4458 2007, 2009 NAPEPLD NM_001122838 264 N-acyl hsa-miR- −0.05 0.94 2007, phosphatidylethanolamine 4458 2009 phospholipase D CASK NM_001126054 265 calcium/calmodulin- hsa-let-7d −0.04 0.91 dependent serine protein kinase (MAGUK family) ELF4 NM_001127197 266 E74-like factor 4 (ets hsa-let-7a −0.17 0.94 2007, domain transcription 2009 factor) TET2 NM_001127208 267 tet oncogene family hsa-miR- −0.16 0.96 member 2 4458 CBX5 NM_001127321 268 chromobox homolog 5 hsa-miR- −0.17 >0.99 4458 CRY2 NM_001127457 269 cryptochrome 2 hsa-miR- −0.12 0.93 2005, (photolyase-like) 4458 2007, 2009 STXBP5 NM_001127715 270 syntaxin binding hsa-let-7d −0.15 0.8 2009 protein 5 (tomosyn) SULF1 NM_001128204 271 sulfatase 1 hsa-miR- −0.1 0.85 2009 4500 SMARCAD1 NM_001128429 272 SWI/SNF-related, hsa-let-7f −0.57 0.95 2005, matrix-associated 2007, actin-dependent 2009 regulator of chromatin, subfamily a, containing DEAD/H box 1 RASGRP1 NM_001128602 273 RAS guanyl releasing hsa-miR- −0.34 0.97 2005, protein 1 (calcium 4458 2007, and DAG-regulated) 2009 PAK1 NM_001128620 274 p21 protein hsa-miR- −0.18 0.78 2005, (Cdc42/Rac)- 4500 2007, activated kinase 1 2009 SPIRE1 NM_001128626 275 spire homolog 1 hsa-let-7a −0.04 0.92 2009 (Drosophila) CALU NM_001130674 276 calumenin hsa-miR- −0.19 0.93 2005, 4458 2007, 2009 STYX NM_001130701 277 serine/threonine/tyrosine hsa-miR- −0.09 0.93 interacting protein 4500 GAS7 NM_001130831 278 growth arrest-specific 7 hsa-miR- −0.28 0.98 2005, 4500 2007, 2009 RTCD1 NM_001130841 279 RNA terminal hsa-miR- −0.2 0.88 phosphate cyclase 4458 domain 1 TGFBR1 NM_001130916 280 transforming growth hsa-let-7f −0.52 >0.99 2005, factor, beta receptor 1 2007, 2009 TTLL6 NM_001130918 281 tubulin tyrosine hsa-miR- −0.26 0.76 ligase-like family, 4458 member 6 TMEM194A NM_001130963 282 transmembrane hsa-let-7a −0.07 0.94 2009 protein 194A MEF2C NM_001131005 283 myocyte enhancer hsa-miR- −0.24 0.87 factor 2C 4458 SAP30L NM_001131062 284 SAP30-like hsa-miR- >−0.02 0.92 4458 CCNJ NM_001134375 285 cyclin J hsa-miR- −0.44 0.94 2005, 4458 2007, 2009 CYB561D1 NM_001134400 286 cytochrome b-561 hsa-let-7d −0.33 0.91 domain containing 1 CDV3 NM_001134422 287 CDV3 homolog hsa-miR- −0.13 0.98 2007, (mouse) 4500 2009 LRRC8B NM_001134476 288 leucine rich repeat hsa-miR- −0.07 0.88 containing 8 family, 4500 member B PBX3 NM_001134778 289 pre-B-cell leukemia hsa-miR-98 −0.32 0.99 2005, homeobox 3 2007, 2009 FNDC3B NM_001135095 290 fibronectin type III hsa-miR- −0.16 0.98 2005, domain containing 3B 4500 2007, 2009 TMPRSS2 NM_001135099 291 transmembrane hsa-let-7b −0.32 0.98 2007, protease, serine 2 2009 HDHD1 NM_001135565 292 haloacid hsa-miR- −0.28 0.62 2005, dehalogenase-like 4500 2007, hydrolase domain 2009 containing 1 LOC221710 NM_001135575 293 hypothetical protein hsa-miR- −0.01 0.78 LOC221710 4458 SPATA2 NM_001135773 294 spermatogenesis hsa-let-7a −0.07 0.94 2005, associated 2 2007, 2009 C9orf7 NM_001135775 295 chromosome 9 open hsa-miR- −0.12 0.92 2005, reading frame 7 4500 2007, 2009 SYT1 NM_001135805 296 synaptotagmin I hsa-miR- −0.16 0.87 2005, 4458 2007, 2009 TMEM2 NM_001135820 297 transmembrane hsa-let-7g −0.41 0.98 2005, protein 2 2007, 2009 PIK3IP1 NM_001135911 298 phosphoinositide-3- hsa-let-7a −0.19 0.85 2005, kinase interacting 2007, protein 1 2009 TTC39C NM_001135993 299 tetratricopeptide hsa-miR- −0.06 0.86 repeat domain 39C 4500 ABL2 NM_001136000 300 v-abl Abelson murine hsa-let-7f −0.23 >0.99 2009 leukemia viral oncogene homolog 2 MICAL3 NM_001136004 301 microtubule hsa-let-7g −0.22 0.83 associated monoxygenase, calponin and LIM domain containing 3 LMLN NM_001136049 302 leishmanolysin-like hsa-miR- −0.13 0.9 (metallopeptidase M8 4500 family) LRIG3 NM_001136051 303 leucine-rich repeats hsa-miR- −0.49 0.96 2005, and immunoglobulin- 4458 2007, like domains 3 2009 ZNF879 NM_001136116 304 zinc finger protein hsa-miR- −0.34 0.95 879 4458 ATXN7L3B NM_001136262 305 ataxin 7-like 3B hsa-miR- >−0.01 0.91 4458 VASH2 NM_001136474 306 vasohibin 2 hsa-let-7d −0.13 0.93 2007, 2009 BTF3L4 NM_001136497 307 basic transcription hsa-miR- −0.12 0.9 2009 factor 3-like 4 4458 SYT2 NM_001136504 308 synaptotagmin II hsa-miR- −0.16 0.94 2009 4500 ATXN1L NM_001137675 309 ataxin 1-like hsa-miR- >−0.02 0.93 4458 NIPA1 NM_001142275 310 non imprinted in hsa-miR- −0.2 0.99 2007, Prader- 4458 2009 Willi/Angelman syndrome 1 RBFOX1 NM_001142333 311 RNA binding protein, hsa-let-7f −0.18 0.86 2005, fox-1 homolog (C. elegans) 1 2007, 2009 GNAL NM_001142339 312 guanine nucleotide hsa-miR- −0.13 0.95 2005, binding protein (G 4500 2007, protein), alpha 2009 activating activity polypeptide, olfactory type SCN4B NM_001142348 313 sodium channel, hsa-miR-98 −0.08 0.93 2009 voltage-gated, type IV, beta CTIF NM_001142397 314 CBP80/20-dependent hsa-let-7a −0.1 0.77 translation initiation factor RPUSD3 NM_001142547 315 RNA pseudouridylate hsa-miR- −0.42 0.89 2007, synthase domain 4500 2009 containing 3 BBX NM_001142568 316 bobby sox homolog hsa-let-7d −0.11 0.81 (Drosophila) CLP1 NM_001142597 317 CLP1, cleavage and hsa-miR- −0.32 0.68 2007 polyadenylation 4458 factor I subunit, homolog (S. cerevisiae) TMOD2 NM_001142885 318 tropomodulin 2 hsa-miR- −0.12 0.98 (neuronal) 4458 PLEKHG6 NM_001144856 319 pleckstrin homology hsa-miR- −0.37 0.98 2007, domain containing, 4458 2009 family G (with RhoGef domain) member 6 LIPT2 NM_001144869 320 lipoyl(octanoyl) hsa-miR- −0.43 0.87 transferase 2 4458 (putative) SLC30A7 NM_001144884 321 solute carrier family hsa-let-7d −0.07 0.9 2009 30 (zinc transporter), member 7 NEDD4L NM_001144964 322 neural precursor cell hsa-miR- −0.06 0.94 expressed, 4500 developmentally down-regulated 4-like PALM3 NM_001145028 323 paralemmin 3 hsa-miR- −0.12 0.91 4458 LRRC10B NM_001145077 324 leucine rich repeat hsa-let-7a −0.07 0.62 containing 10B GRID2IP NM_001145118 325 glutamate receptor, hsa-miR- −0.26 0.94 ionotropic, delta 2 4458 (Grid2) interacting protein CDK6 NM_001145306 326 cyclin-dependent hsa-miR- −0.08 0.85 kinase 6 4458 ZNF566 NM_001145343 327 zinc finger protein hsa-let-7f −0.25 0.93 2009 566 ZNF652 NM_001145365 328 zinc finger protein hsa-miR- −0.15 >0.99 652 4458 POTEM NM_001145442 329 POTE ankyrin hsa-miR- −0.22 <0.1 domain family, 4500 member M ZNF200 NM_001145446 330 zinc finger protein hsa-let-7d −0.37 >0.99 2009 200 SOX6 NM_001145811 331 SRY (sex determining hsa-let-7d −0.16 0.72 region Y)-box 6 SLCO5A1 NM_001146008 332 solute carrier organic hsa-miR- −0.08 0.81 2005, anion transporter 4500 2007, family, member 5A1 2009 NEK3 NM_001146099 333 NIMA (never in hsa-miR- −0.35 0.91 2009 mitosis gene a)- 4500 related kinase 3 SLC6A15 NM_001146335 334 solute carrier family 6 hsa-miR- −0.15 0.94 (neutral amino acid 4500 transporter), member 15 SLC25A4 NM_001151 335 solute carrier family hsa-miR- −0.15 0.94 2005, 25 (mitochondrial 4500 2007 carrier; adenine nucleotide translocator), member 4 KLF8 NM_001159296 336 Kruppel-like factor 8 hsa-miR- −0.11 0.81 4458 BEGAIN NM_001159531 337 brain-enriched hsa-miR- −0.36 0.99 2005, guanylate kinase- 4458 2007, associated homolog 2009 (rat) BEND4 NM_001159547 338 BEN domain hsa-miR-98 −0.24 >0.99 2009 containing 4 SYNCRIP NM_001159673 339 synaptotagmin hsa-miR- −0.29 0.96 binding, cytoplasmic 4458 RNA interacting protein BZW2 NM_001159767 340 basic leucine zipper hsa-let-7a −0.24 0.81 2007, and W2 domains 2 2009 CANT1 NM_001159772 341 calcium activated hsa-miR- −0.19 0.89 2009 nucleotidase 1 4458 ZNF583 NM_001159860 342 zinc finger protein hsa-let-7f −0.44 0.98 2007, 583 2009 RNF170 NM_001160223 343 ring finger protein hsa-let-7d −0.41 0.98 170 PANX2 NM_001160300 344 pannexin 2 hsa-miR- −0.1 0.92 2005, 4458 2007, 2009 TMC7 NM_001160364 345 transmembrane hsa-let-7d −0.12 0.92 2005, channel-like 7 2007, 2009 IGF2BP1 NM_001160423 346 insulin-like growth hsa-miR- −0.4 >0.99 2007, factor 2 mRNA 4500 2009 binding protein 1 SYNC NM_001161708 347 syncoilin, hsa-miR- −0.48 <0.1 intermediate filament 4500 protein SULF2 NM_001161841 348 sulfatase 2 hsa-miR- −0.12 0.91 4458 APBA1 NM_001163 349 amyloid beta (A4) hsa-let-7a −0.11 0.94 precursor protein- binding, family A, member 1 CECR6 NM_001163079 350 cat eye syndrome hsa-let-7d −0.14 0.95 2005, chromosome region, 2007, candidate 6 2009 PCYT1B NM_001163264 351 phosphate hsa-miR- >−0.02 0.91 2007, cytidylyltransferase 1, 4458 2009 choline, beta CPA4 NM_001163446 352 carboxypeptidase A4 hsa-miR- −0.37 0.93 2005, 4458 2007, 2009 GTF2I NM_001163636 353 general transcription hsa-miR- −0.2 0.85 2007, factor IIi 4458 2009 DLC1 NM_001164271 354 deleted in liver cancer 1 hsa-miR- −0.22 >0.99 2005, 4458 2007, 2009 SLC37A4 NM_001164277 355 solute carrier family hsa-let-7d −0.11 0.7 37 (glucose-6- phosphate transporter), member 4 ANKRD33B NM_001164440 356 ankyrin repeat hsa-miR- >−0.03 0.25 domain 33B 4458 C16orf52 NM_001164579 357 chromosome 16 open hsa-miR- −0.09 0.83 reading frame 52 4458 KIAA1549 NM_001164665 358 KIAA1549 hsa-miR- >−0.02 0.94 2009 4458 PITPNM3 NM_001165966 359 PITPNM family hsa-miR- >−0.02 0.94 member 3 4458 EPB41 NM_001166005 360 erythrocyte hsa-let-7a −0.06 0.76 2009 membrane protein band 4.1 (elliptocytosis 1, RH- linked) CEP120 NM_001166226 361 centrosomal protein hsa-miR- −0.22 0.92 2007, 120 kDa 4458 2009 GRIK2 NM_001166247 362 glutamate receptor, hsa-miR- −0.12 0.86 2005, ionotropic, kainate 2 4500 2007, 2009 SPATA13 NM_001166271 363 spermatogenesis hsa-miR- >−0.02 0.64 associated 13 4458 TRAPPC1 NM_001166621 364 trafficking protein hsa-miR- N/A 0.12 2005, particle complex 1 4458 2007, 2009 TMED5 NM_001167830 365 transmembrane hsa-miR- −0.11 0.95 2005, emp24 protein 4500 2007, transport domain 2009 containing 5 SBNO1 NM_001167856 366 strawberry notch hsa-miR- −0.17 0.95 homolog 1 4458 (Drosophila) TIMM17B NM_001167947 367 translocase of inner hsa-miR- −0.16 0.93 2005, mitochondrial 4458 2007, membrane 17 2009 homolog B (yeast) GPR156 NM_001168271 368 G protein-coupled hsa-miR- −0.21 0.95 receptor 156 4458 EDN1 NM_001168319 369 endothelin 1 hsa-miR- −0.31 0.86 2009 4500 TXLNG NM_001168683 370 taxilin gamma hsa-miR- −0.32 0.95 4500 TMEM135 NM_001168724 371 transmembrane hsa-let-7a −0.11 0.93 protein 135 AFF2 NM_001169122 372 AF4/FMR2 family, hsa-miR- −0.22 0.92 2009 member 2 4458 GPR137 NM_001170726 373 G protein-coupled hsa-let-7b −0.16 0.67 2003, receptor 137 2007, 2009 LCOR NM_001170765 374 ligand dependent hsa-miR- −0.14 0.96 2007, nuclear receptor 4500 2009 corepressor IGSF1 NM_001170963 375 immunoglobulin hsa-let-7f −0.38 0.93 2009 superfamily, member 1 STRBP NM_001171137 376 spermatid perinuclear hsa-miR- −0.2 0.89 2005, RNA binding protein 4458 2007, 2009 C3orf52 NM_001171747 377 chromosome 3 open hsa-miR- −0.23 0.85 2009 reading frame 52 4458 CSRNP3 NM_001172173 378 cysteine-serine-rich hsa-let-7c −0.05 0.87 nuclear protein 3 OLR1 NM_001172632 379 oxidized low density hsa-miR- −0.12 0.88 2005, lipoprotein (lectin- 4458 2007, like) receptor 1 2009 RAB40C NM_001172663 380 RAB40C, member hsa-let-7a −0.1 0.91 2005, RAS oncogene family 2007, 2009 ZNF347 NM_001172674 381 zinc finger protein hsa-miR- −0.41 <0.1 347 4458 ZNF641 NM_001172681 382 zinc finger protein hsa-miR- −0.2 0.93 641 4458 PPARGC1B NM_001172698 383 peroxisome hsa-miR- −0.31 >0.99 2005, proliferator-activated 4500 2007, receptor gamma, 2009 coactivator 1 beta PPP1R16B NM_001172735 384 protein phosphatase 1, hsa-miR- −0.07 0.94 2005, regulatory (inhibitor) 4458 2007, subunit 16B 2009 FOXP2 NM_001172766 385 forkhead box P2 hsa-miR- −0.33 >0.99 4500 CRBN NM_001173482 386 cereblon hsa-miR- −0.2 0.74 4458 LMX1A NM_001174069 387 LIM homeobox hsa-miR-98 −0.16 0.92 2007, transcription factor 1, 2009 alpha POLL NM_001174084 388 polymerase (DNA hsa-miR- −0.31 <0.1 2009 directed), lambda 4458 NCOA3 NM_001174087 389 nuclear receptor hsa-miR- −0.1 0.84 2005, coactivator 3 4458 2007 TRPM6 NM_001177310 390 transient receptor hsa-miR- −0.2 0.98 2005, potential cation 4458 2007, channel, subfamily 2009 M, member 6 CPEB2 NM_001177381 391 cytoplasmic hsa-let-7b −0.21 0.98 2005, polyadenylation 2007, element binding 2009 protein 2 HDX NM_001177478 392 highly divergent hsa-let-7g −0.38 0.97 homeobox PPP2R2A NM_001177591 393 protein phosphatase 2, hsa-miR- −0.19 0.94 regulatory subunit B, 4458 alpha STX3 NM_001178040 394 syntaxin 3 hsa-let-7g −0.41 0.98 2007, 2009 PARP8 NM_001178055 395 poly (ADP-ribose) hsa-miR- −0.23 0.98 polymerase family, 4458 member 8 BCAT1 NM_001178091 396 branched chain hsa-miR- −0.1 0.95 2009 amino-acid 4500 transaminase 1, cytosolic CPEB3 NM_001178137 397 cytoplasmic hsa-miR- −0.15 0.96 2005, polyadenylation 4458 2007, element binding 2009 protein 3 SLAMF6 NM_001184714 398 SLAM family hsa-miR- −0.22 0.88 2007, member 6 4458 2009 PEX11B NM_001184795 399 peroxisomal hsa-miR- −0.34 0.51 2009 biogenesis factor 11 4458 beta PHF8 NM_001184896 400 PHD finger protein 8 hsa-miR- >−0.02 0.92 2005, 4458 2007, 2009 CLDN12 NM_001185072 401 claudin 12 hsa-miR- −0.34 0.98 2005, 4458 2007, 2009 BACH1 NM_001186 402 BTB and CNC hsa-let-7c −0.31 >0.99 2005, homology 1, basic 2007, leucine zipper 2009 transcription factor 1 ATG16L1 NM_001190266 403 ATG16 autophagy hsa-miR- −0.09 0.92 2007, related 16-like 1 (S. cerevisiae) 4458 2009 NCOR1 NM_001190440 404 nuclear receptor hsa-miR- −0.05 0.92 corepressor 1 4458 COL11A1 NM_001190709 405 collagen, type XI, hsa-miR- −0.1 0.77 alpha 1 4458 YAF2 NM_001190977 406 YY1 associated factor 2 hsa-let-7a −0.05 0.94 2009 BCL2L1 NM_001191 407 BCL2-like 1 hsa-miR- −0.2 0.9 2005, 4458 2007, 2009 IKBKE NM_001193321 408 inhibitor of kappa hsa-let-7b −0.13 0.94 2005, light polypeptide gene 2007, enhancer in B-cells, 2009 kinase epsilon SECISBP2L NM_001193489 409 SECIS binding hsa-miR- −0.08 0.81 protein 2-like 4458 SLC1A4 NM_001193493 410 solute carrier family 1 hsa-let-7d −0.05 0.98 2009 (glutamate/neutral amino acid transporter), member 4 SLC30A6 NM_001193513 411 solute carrier family hsa-miR- −0.31 0.92 30 (zinc transporter), 4458 member 6 POGZ NM_001194937 412 pogo transposable hsa-miR- −0.16 0.88 2005, element with ZNF 4458 2007, domain 2009 PTPRU NM_001195001 413 protein tyrosine hsa-let-7a −0.14 0.92 2009 phosphatase, receptor type, U ANKRD28 NM_001195098 414 ankyrin repeat hsa-miR- −0.2 0.84 2009 domain 28 4458 PTP4A2 NM_001195100 415 protein tyrosine hsa-let-7b −0.07 0.75 phosphatase type IVA, member 2 LOC100507421 NM_001195278 416 transmembrane hsa-miR- −0.06 0.85 protein 178-like 4458 DICER1 NM_001195573 417 dicer 1, ribonuclease hsa-miR- −0.05 >0.99 2009 type III 4458 MLLT10 NM_001195626 418 myeloid/lymphoid or hsa-let-7i −0.15 0.86 2005, mixed-lineage 2007, leukemia (trithorax 2009 homolog, Drosophila); translocated to, 10 TGFBR3 NM_001195683 419 transforming growth hsa-let-7g −0.39 0.98 factor, beta receptor III PLD5 NM_001195811 420 phospholipase D hsa-miR-98 −0.18 0.86 family, member 5 PLEKHA8 NM_001197026 421 pleckstrin homology hsa-let-7a −0.32 0.99 domain containing, family A (phosphoinositide binding specific) member 8 DPYSL3 NM_001197294 422 dihydropyrimidinase- hsa-miR- −0.03 0.84 2009 like 3 4500 GABPA NM_001197297 423 GA binding protein hsa-miR- −0.09 0.92 2007, transcription factor, 4500 2009 alpha subunit 60 kDa PRDM1 NM_001198 424 PR domain containing hsa-let-7a −0.05 0.74 2005, 1, with ZNF domain 2007, 2009 RUNX1T1 NM_001198625 425 runt-related hsa-miR- −0.05 0.91 transcription factor 1; 4458 translocated to, 1 (cyclin D-related) POU2F1 NM_001198783 426 POU class 2 hsa-miR- −0.02 >0.99 homeobox 1 4458 A1CF NM_001198818 427 APOBEC1 hsa-miR- −0.11 <0.1 complementation 4500 factor ABCC10 NM_001198934 428 ATP-binding cassette, hsa-miR- −0.16 0.82 2005, sub-family C 4458 2007 (CFTR/MRP), member 10 SMAP2 NM_001198978 429 small ArfGAP2 hsa-miR- −0.21 0.82 2007, 4458 2009 AMMECR1L NM_001199140 430 AMME chromosomal hsa-let-7d −0.11 <0.1 2007, region gene 1-like 2009 TOR1AIP2 NM_001199260 431 torsin A interacting hsa-miR- >−0.03 0.98 protein 2 4458 UCHL5 NM_001199261 432 ubiquitin carboxyl- hsa-let-7f −0.04 <0.1 terminal hydrolase L5 PHOSPHO2- NM_001199290 433 PHOSPHO2- hsa-let-7f −0.2 0.95 KLHL23 KLHL23 readthrough CNOT2 NM_001199302 434 CCR4-NOT hsa-let-7d −0.14 0.86 2007, transcription 2009 complex, subunit 2 MUTED NM_001199322 435 muted homolog hsa-let-7c −0.1 0.82 2009 (mouse) CPD NM_001199775 436 carboxypeptidase D hsa-let-7d −0.18 0.95 2005, 2007, 2009 POC1B- NM_001199781 437 POC1B-GALNT4 hsa-let-7a −0.1 0.84 GALNT4 readthrough EGR3 NM_001199880 438 early growth response 3 hsa-miR- >−0.03 0.67 2005, 4458 2007, 2009 DNAL1 NM_001201366 439 dynein, axonemal, hsa-miR- −0.03 0.94 2009 light chain 1 4458 RNF7 NM_001201370 440 ring finger protein 7 hsa-miR- −0.18 0.94 2005, 4458 2007, 2009 TRMT1L NM_001202423 441 TRM1 tRNA hsa-miR- −0.16 0.65 methyltransferase 1- 4458 like HSPE1- NM_001202485 442 HSPE1-MOBKL3 hsa-let-7a −0.12 0.93 MOBKL3 readthrough UBE2G2 NM_001202489 443 ubiquitin-conjugating hsa-miR- −0.14 0.94 2009 enzyme E2G 2 4458 MXD1 NM_001202513 444 MAX dimerization hsa-miR- −0.23 0.94 2007, protein 1 4458 2009 CUX1 NM_001202543 445 cut-like homeobox 1 hsa-miR- −0.05 0.77 4458 SEMA4G NM_001203244 446 sema domain, hsa-let-7a −0.22 0.9 2005, immunoglobulin 2007, domain (Ig), 2009 transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4G EZH2 NM_001203247 447 enhancer of zeste hsa-miR- N/A 0.86 2005, homolog 2 4458 2007, (Drosophila) 2009 PPT2 NM_001204103 448 palmitoyl-protein hsa-miR- −0.29 <0.1 thioesterase 2 4458 MDM4 NM_001204171 449 Mdm4 p53 binding hsa-let-7a −0.27 >0.99 protein homolog (mouse) RGS6 NM_001204416 450 regulator of G-protein hsa-miR- −0.22 0.95 2009 signaling 6 4458 NPEPL1 NM_001204872 451 aminopeptidase-like 1 hsa-let-7f −0.15 0.94 2005, 2007, 2009 PBX1 NM_001204961 452 pre-B-cell leukemia hsa-let-7g −0.28 0.94 homeobox 1 KLF9 NM_001206 453 Kruppel-like factor 9 hsa-miR- −0.18 0.92 2005, 4500 2007, 2009 CD86 NM_001206924 454 CD86 molecule hsa-miR- −0.2 0.6 2009 4500 POU2F2 NM_001207025 455 POU class 2 hsa-miR- −0.14 0.89 2007, homeobox 2 4458 2009 CLASP2 NM_001207044 456 cytoplasmic linker hsa-let-7g −0.14 0.94 2005, associated protein 2 2007, 2009 BZW1 NM_001207067 457 basic leucine zipper hsa-let-7f −0.48 0.99 2005, and W2 domains 1 2007, 2009 MEIS2 NM_001220482 458 Meis homeobox 2 hsa-miR- −0.18 0.86 2005, 4458 2007, 2009 CCNT2 NM_001241 459 cyclin T2 hsa-miR- −0.1 0.76 4458 ATAD2B NM_001242338 460 ATPase family, AAA hsa-miR- >−0.03 0.66 2009 domain containing 2B 4458 FAM59A NM_001242409 461 family with sequence hsa-let-7f −0.17 0.94 similarity 59, member A FBXO32 NM_001242463 462 F-box protein 32 hsa-let-7b −0.26 0.95 MAP4K4 NM_001242559 463 mitogen-activated hsa-miR- −0.2 0.99 2005, protein kinase kinase 4458 2007, kinase kinase 4 2009 NXT2 NM_001242617 464 nuclear transport hsa-let-7g −0.21 0.86 2005, factor 2-like export 2007, factor 2 2009 GFOD1 NM_001242628 465 glucose-fructose hsa-miR- −0.29 <0.1 oxidoreductase 4458 domain containing 1 ARHGEF38 NM_001242729 466 Rho guanine hsa-miR- −0.53 0.94 nucleotide exchange 4500 factor (GEF) 38 ZNF322A NM_001242797 467 zinc finger protein hsa-let-7a −0.47 0.96 2009 322A CHD4 NM_001273 468 chromodomain hsa-miR- −0.17 0.83 2005, helicase DNA binding 4500 2007, protein 4 2009 CHUK NM_001278 469 conserved helix-loop- hsa-miR- −0.27 0.74 helix ubiquitous 4500 kinase AP1S1 NM_001283 470 adaptor-related hsa-miR- −0.27 0.88 2005, protein complex 1, 4458 2007, sigma 1 subunit 2009 DUSP4 NM_001394 471 dual specificity hsa-miR- −0.17 0.94 2007, phosphatase 4 4500 2009 DUSP9 NM_001395 472 dual specificity hsa-miR- −0.07 0.93 2005, phosphatase 9 4500 2007, 2009 DYRK1A NM_001396 473 dual-specificity hsa-miR- −0.15 0.84 2005, tyrosine-(Y)- 4500 2007, phosphorylation 2009 regulated kinase 1A GATM NM_001482 474 glycine hsa-let-7a −0.44 0.96 2009 amidinotransferase (L-arginine:glycine amidinotransferase) ACVR2A NM_001616 475 activin A receptor, hsa-let-7a −0.24 0.98 2007, type IIA 2009 AKT2 NM_001626 476 v-akt marine hsa-let-7i −0.15 0.88 2009 thymoma viral oncogene homolog 2 ARL4D NM_001661 477 ADP-ribosylation hsa-miR- −0.19 0.94 2009 factor-like 4D 4500 POLR3D NM_001722 478 polymerase (RNA) III hsa-miR- −0.28 0.91 2007, (DNA directed) 4500 2009 polypeptide D, 44 kDa CCND2 NM_001759 479 cyclin D2 hsa-miR- −0.14 >0.99 2005, 4458 2007, 2009 CCNF NM_001761 480 cyclin F hsa-let-7d −0.4 0.92 2009 CDC25A NM_001789 481 cell division cycle 25 hsa-miR- −0.42 0.9 2005, homolog A (S. pombe) 4458 2007, 2009 CCR7 NM_001838 482 chemokine (C-C hsa-let-7f −0.36 0.96 2005, motif) receptor 7 2007, 2009 COL4A1 NM_001845 483 collagen, type IV, hsa-miR- −0.15 0.92 2005, alpha 1 4458 2007, 2009 COL4A2 NM_001846 484 collagen, type IV, hsa-miR-98 −0.17 0.94 2005, alpha 2 2007, 2009 COL4A6 NM_001847 485 collagen, type IV, hsa-miR- −0.34 <0.1 2009 alpha 6 4458 COL9A3 NM_001853 486 collagen, type IX, hsa-let-7a −0.11 0.86 2009 alpha 3 COL15A1 NM_001855 487 collagen, type XV, hsa-miR- −0.18 0.93 2005, alpha 1 4500 2007, 2009 SLC31A1 NM_001859 488 solute carrier family hsa-miR- −0.12 0.94 2009 31 (copper 4458 transporters), member 1 SLC31A2 NM_001860 489 solute carrier family hsa-let-7a −0.17 0.71 2005, 31 (copper 2007 transporters), member 2 MASP1 NM_001879 490 mannan-binding hsa-let-7a −0.34 0.94 2007, lectin serine peptidase 2009 1 (C4/C2 activating component of Ra- reactive factor) CTPS NM_001905 491 CTP synthase hsa-miR- −0.19 0.79 4458 DLST NM_001933 492 dihydrolipoamide S- hsa-miR- −0.17 0.95 2005, succinyltransferase 4500 2007, (E2 component of 2- 2009 oxo-glutarate complex) DSG3 NM_001944 493 desmoglein 3 hsa-miR- −0.16 <0.1 4500 HBEGF NM_001945 494 heparin-binding EGF- hsa-miR- −0.17 0.73 like growth factor 4500 DUSP7 NM_001947 495 dual specificity hsa-let-7b −0.07 0.94 phosphatase 7 ELK4 NM_001973 496 ELK4, ETS-domain hsa-miR- −0.14 0.94 protein (SRF 4458 accessory protein 1) EZH1 NM_001991 497 enhancer of zeste hsa-let-7a −0.14 0.88 2009 homolog 1 (Drosophila) GLRX NM_002064 498 glutaredoxin hsa-let-7d −0.23 0.78 2009 (thioltransferase) GNS NM_002076 499 glucosamine (N- hsa-miR- >−0.01 0.88 2005, acetyl)-6-sulfatase 4458 2007, 2009 HLF NM_002126 500 hepatic leukemia hsa-miR- −0.06 0.87 2007, factor 4500 2009 HMGA1 NM_002131 501 high mobility group hsa-let-7i −0.25 0.94 2005, AT-hook 1 2007, 2009 IDH2 NM_002168 502 isocitrate hsa-let-7d −0.12 0.83 2005, dehydrogenase 2 2007 (NADP+), mitochondrial IL13 NM_002188 503 interleukin 13 hsa-miR- −0.32 0.98 2005, 4500 2007, 2009 ITGB8 NM_002214 504 integrin, beta 8 hsa-let-7i −0.1 0.94 2007, 2009 KCNA6 NM_002235 505 potassium voltage- hsa-miR- >−0.03 0.44 2009 gated channel, shaker- 4458 related subfamily, member 6 KPNA1 NM_002264 506 karyopherin alpha 1 hsa-miR- −0.15 0.93 2007, (importin alpha 5) 4458 2009 KPNA4 NM_002268 507 karyopherin alpha 4 hsa-miR- −0.08 0.97 2005, (importin alpha 3) 4458 2007 LBR NM_002296 508 lamin B receptor hsa-miR- −0.21 0.98 2009 4458 LY75 NM_002349 509 lymphocyte antigen hsa-let-7d −0.17 0.8 2009 75 MAP3K3 NM_002401 510 mitogen-activated hsa-miR- −0.06 0.95 2005, protein kinase kinase 4458 2007, kinase 3 2009 MSR1 NM_002445 511 macrophage hsa-let-7a −0.37 0.98 scavenger receptor 1 NGF NM_002506 512 nerve growth factor hsa-miR- −0.34 0.93 2009 (beta polypeptide) 4458 NOVA1 NM_002515 513 neuro-oncological hsa-let-7d −0.11 0.92 2005, ventral antigen 1 2007, 2009 NRAS NM_002524 514 neuroblastoma RAS hsa-miR- −0.35 >0.99 2005, viral (v-ras) oncogene 4500 2007, homolog 2009 P2RX1 NM_002558 515 purinergic receptor hsa-miR- −0.12 0.9 2009 P2X, ligand-gated ion 4458 channel, 1 PAPPA NM_002581 516 pregnancy-associated hsa-miR-98 −0.2 >0.99 2005, plasma protein A, 2007, pappalysin 1 2009 PBX2 NM_002586 517 pre-B-cell leukemia hsa-miR- −0.22 >0.99 2005, homeobox 2 4500 2007, 2009 PDGFB NM_002608 518 platelet-derived hsa-miR- −0.11 0.88 2005, growth factor beta 4458 2007, polypeptide 2009 PIGA NM_002641 519 phosphatidylinositol hsa-miR- −0.29 0.94 2005, glycan anchor 4500 2007, biosynthesis, class A 2009 PLAGL2 NM_002657 520 pleiomorphic hsa-miR- −0.12 0.91 2005, adenoma gene-like 2 4500 2007, 2009 MAPK6 NM_002748 521 mitogen-activated hsa-let-7b −0.38 0.94 2005, protein kinase 6 2007, 2009 MAPK11 NM_002751 522 mitogen-activated hsa-miR- −0.11 0.79 2009 protein kinase 11 4458 MAPK9 NM_002752 523 mitogen-activated hsa-miR- −0.05 0.77 protein kinase 9 4458 PTPRO NM_002848 524 protein tyrosine hsa-let-7d −0.14 0.88 2009 phosphatase, receptor type, O RALB NM_002881 525 v-ral simian leukemia hsa-miR- −0.17 0.94 2009 viral oncogene 4458 homolog B (ras related; GTP binding protein) RBMS1 NM_002897 526 RNA binding motif, hsa-let-7d −0.25 0.96 single stranded interacting protein 1 RBMS2 NM_002898 527 RNA binding motif, hsa-let-7a −0.1 0.98 single stranded interacting protein 2 RCN1 NM_002901 528 reticulocalbin 1, EF- hsa-let-7d −0.17 0.85 2009 hand calcium binding domain RDX NM_002906 529 radixin hsa-let-7a −0.25 0.75 2005, 2007, 2009 RGS16 NM_002928 530 regulator of G-protein hsa-miR- −0.31 0.98 2005, signaling 16 4500 2007, 2009 S100A8 NM_002964 531 S100 calcium binding hsa-miR- −0.18 0.69 protein A8 4500 CCL3 NM_002983 532 chemokine (C-C hsa-miR- −0.23 0.87 2009 motif) ligand 3 4458 ST3GAL1 NM_003033 533 ST3 beta-galactoside hsa-miR- >−0.01 0.89 alpha-2,3- 4458 sialyltransferase 1 ST8SIA1 NM_003034 534 ST8 alpha-N-acetyl- hsa-let-7f −0.29 0.94 2009 neuraminide alpha- 2,8-sialyltransferase 1 SLC6A1 NM_003042 535 solute carrier family 6 hsa-miR- −0.19 0.95 2005, (neurotransmitter 4458 2007, transporter, GABA), 2009 member 1 SMARCC1 NM_003074 536 SWI/SNF related, hsa-let-7g −0.13 0.91 2005, matrix associated, 2007, actin dependent 2009 regulator of chromatin, subfamily c, member 1 SNX1 NM_003099 537 sorting nexin 1 hsa-miR- −0.2 <0.1 2009 4458 STRN NM_003162 538 striatin, calmodulin hsa-miR- −0.14 0.95 binding protein 4458 TEAD3 NM_003214 539 TEA domain family hsa-miR- −0.08 0.91 2007, member 3 4458 2009 THBS1 NM_003246 540 thrombospondin 1 hsa-let-7c −0.16 0.86 2009 THRSP NM_003251 541 thyroid hormone hsa-let-7d −0.62 0.74 2009 responsive VSNL1 NM_003385 542 visinin-like 1 hsa-miR- −0.11 0.79 2005, 4458 2007, 2009 ZNF202 NM_003455 543 zinc finger protein hsa-let-7d −0.36 <0.1 202 BSN NM_003458 544 bassoon (presynaptic hsa-let-7a −0.09 0.94 2009 cytomatrix protein) MLL2 NM_003482 545 myeloid/lymphoid or hsa-miR- −0.26 0.98 2007, mixed-lineage 4458 2009 leukemia 2 HMGA2 NM_003483 546 high mobility group hsa-miR- −1.04 >0.99 2005, AT-hook 2 4458 2007, 2009 SNN NM_003498 547 stannin hsa-miR- −0.15 0.87 2005, 4458 2007, 2009 EEA1 NM_003566 548 early endosome hsa-miR- −0.21 0.94 2007, antigen 1 4458 2009 ZNF282 NM_003575 549 zinc finger protein hsa-miR- >−0.02 0.94 2009 282 4458 DYRK2 NM_003583 550 dual-specificity hsa-miR- −0.12 0.87 2009 tyrosine-(Y)- 4500 phosphorylation regulated kinase 2 SLC4A7 NM_003615 551 solute carrier family hsa-let-7g −0.02 0.81 2005, 4, sodium bicarbonate 2007 cotransporter, member 7 MAP4K3 NM_003618 552 mitogen-activated hsa-miR-98 −0.46 0.96 2005, protein kinase kinase 2007, kinase kinase 3 2009 NDST2 NM_003635 553 N-deacetylase/N- hsa-miR- −0.32 0.96 2005, sulfotransferase 4458 2007, (heparan 2009 glucosaminyl) 2 IKBKAP NM_003640 554 inhibitor of kappa hsa-miR- −0.27 0.93 2005, light polypeptide gene 4458 2007, enhancer in B-cells, 2009 kinase complex- associated protein CHRD NM_003741 555 chordin hsa-miR- −0.15 0.87 2005, 4458 2007 NCOA1 NM_003743 556 nuclear receptor hsa-let-7d −0.07 0.7 2005, coactivator 1 2007 IRS2 NM_003749 557 insulin receptor hsa-miR- −0.28 0.98 2005, substrate 2 4458 2007, 2009 GALNT4 NM_003774 558 UDP-N-acetyl-alpha- hsa-let-7a −0.1 0.84 2009 D- galactosamine:polypeptide N- acetylgalactosaminyltransferase 4 (GalNAc-T4) RNMT NM_003799 559 RNA (guanine-7-) hsa-miR- −0.31 <0.1 methyltransferase 4458 TNFSF9 NM_003811 560 tumor necrosis factor hsa-let-7d −0.35 0.98 2009 (ligand) superfamily, member 9 SNAP23 NM_003825 561 synaptosomal- hsa-miR- −0.26 0.93 2005, associated protein, 4500 2007, 23 kDa 2009 RIOK3 NM_003831 562 RIO kinase 3 (yeast) hsa-miR- −0.26 0.94 2005, 4500 2007, 2009 SUCLG2 NM_003848 563 succinate-CoA ligase, hsa-let-7a −0.14 0.89 2009 GDP-forming, beta subunit EIF2S2 NM_003908 564 eukaryotic translation hsa-miR- −0.22 0.92 2009 initiation factor 2, 4458 subunit 2 beta, 38 kDa MBD2 NM_003927 565 methyl-CpG binding hsa-let-7f −0.29 >0.99 domain protein 2 WASL NM_003941 566 Wiskott-Aldrich hsa-let-7d −0.17 0.87 2009 syndrome-like RNF8 NM_003958 567 ring finger protein 8 hsa-miR- −0.1 0.68 4500 OSMR NM_003999 568 oncostatin M receptor hsa-miR- −0.27 0.94 2005, 4458 2007, 2009 E2F2 NM_004091 569 E2F transcription hsa-let-7d −0.28 0.94 2009 factor 2 FGF11 NM_004112 570 fibroblast growth hsa-miR-98 −0.26 0.93 2005, factor 11 2007, 2009 TARBP2 NM_004178 571 TAR (HIV-1) RNA hsa-miR- −0.2 0.93 2009 binding protein 2 4458 SEMA3F NM_004186 572 sema domain, hsa-miR- −0.16 0.72 2005, immunoglobulin 4458 2007 domain (Ig), short basic domain, secreted, (semaphorin) 3F SYT7 NM_004200 573 synaptotagmin VII hsa-miR-98 −0.25 0.98 2007, 2009 AURKB NM_004217 574 aurora kinase B hsa-miR- −0.26 0.78 4458 CYTH3 NM_004227 575 cytohesin 3 hsa-miR- −0.02 0.9 2005, 4458 2007, 2009 SEMA4F NM_004263 576 sema domain, hsa-miR- −0.4 0.97 2009 immunoglobulin 4500 domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4F CHST3 NM_004273 577 carbohydrate hsa-miR- −0.11 0.99 2009 (chondroitin 6) 4458 sulfotransferase 3 AKAP6 NM_004274 578 A kinase (PRKA) hsa-let-7c −0.28 0.95 2005, anchor protein 6 2007, 2009 SLC25A27 NM_004277 579 solute carrier family hsa-miR- −0.29 0.95 2005, 25, member 27 4458 2007, 2009 ACVR1B NM_004302 580 activin A receptor, hsa-let-7g −0.12 0.95 2005, type IB 2007, 2009 CASP3 NM_004346 581 caspase 3, apoptosis- hsa-let-7b −0.4 0.99 2005, related cysteine 2007, peptidase 2009 CDC34 NM_004359 582 cell division cycle 34 hsa-miR- −0.47 >0.99 2005, homolog (S. cerevisiae) 4500 2007, 2009 DUSP1 NM_004417 583 dual specificity hsa-miR- −0.18 0.87 2005, phosphatase 1 4500 2007, 2009 DVL3 NM_004423 584 dishevelled, dsh hsa-let-7f −0.41 0.89 2009 homolog 3 (Drosophila) EPHA4 NM_004438 585 EPH receptor A4 hsa-miR- −0.18 0.87 2005, 4500 2007, 2009 FGF5 NM_004464 586 fibroblast growth hsa-miR- −0.11 0.93 2009 factor 5 4458 GALNT2 NM_004481 587 UDP-N-acetyl-alpha- hsa-miR- −0.18 0.94 2005, D- 4500 2007, galactosamine:polypeptide 2009 N- acetylgalactosaminyltransferase 2 (GalNAc-T2) USP6 NM_004505 588 ubiquitin specific hsa-let-7a −0.18 0.92 2005, peptidase 6 (Tre-2 2007, oncogene) 2009 NAP1L1 NM_004537 589 nucleosome assembly hsa-let-7d −0.41 >0.99 2005, protein 1-like 1 2007, 2009 NRTN NM_004558 590 neurturin hsa-miR- N/A 0.85 2007, 4458 2009 RPS6KA3 NM_004586 591 ribosomal protein S6 hsa-miR-98 −0.1 0.94 2005, kinase, 90 kDa, 2007, polypeptide 3 2009 COIL NM_004645 592 coilin hsa-miR- −0.5 0.96 2005, 4500 2007, 2009 KCNQ4 NM_004700 593 potassium voltage- hsa-let-7d −0.18 0.94 gated channel, KQT- like subfamily, member 4 NUMBL NM_004756 594 numb homolog hsa-miR- −0.04 0.94 2005, (Drosophila)-like 4500 2007, 2009 NDST3 NM_004784 595 N-deacetylase/N- hsa-let-7d −0.18 0.83 sulfotransferase (heparan glucosaminyl) 3 POLR2D NM_004805 596 polymerase (RNA) II hsa-let-7b −0.42 <0.1 2009 (DNA directed) polypeptide D HAND1 NM_004821 597 heart and neural crest hsa-let-7a −0.44 0.98 2005, derivatives expressed 1 2007, 2009 NTN1 NM_004822 598 netrin 1 hsa-miR- −0.26 0.84 2009 4500 ONECUT2 NM_004852 599 one cut homeobox 2 hsa-miR- −0.13 >0.99 2007, 4500 2009 AKAP5 NM_004857 600 A kinase (PRKA) hsa-miR- >−0.03 0.72 2009 anchor protein 5 4458 IGDCC3 NM_004884 601 immunoglobulin hsa-miR- −0.72 >0.99 2003, superfamily, DCC 4500 2007, subclass, member 3 2009 SEC24C NM_004922 602 SEC24 family, hsa-miR-98 −0.1 0.82 2005, member C (S. cerevisiae) 2007, 2009 DAPK1 NM_004938 603 death-associated hsa-let-7g −0.18 0.93 2009 protein kinase 1 DOCK3 NM_004947 604 dedicator of hsa-miR- −0.07 0.9 2005, cytokinesis 3 4458 2007, 2009 KCNC1 NM_004976 605 potassium voltage- hsa-miR- −0.1 0.91 2009 gated channel, Shaw- 4458 related subfamily, member 1 NME4 NM_005009 606 non-metastatic cells 4, hsa-let-7d −0.19 0.94 2003, protein expressed in 2005, 2007, 2009 QARS NM_005051 607 glutaminyl-tRNA hsa-let-7i −0.37 0.2 2005, synthetase 2007, 2009 SCD NM_005063 608 stearoyl-CoA hsa-miR-98 −0.33 0.95 2007, desaturase (delta-9- 2009 desaturase) SIM2 NM_005069 609 single-minded hsa-let-7d −0.08 0.9 2009 homolog 2 (Drosophila) ADRBK2 NM_005160 610 adrenergic, beta, hsa-miR-98 −0.15 0.89 2009 receptor kinase 2 CBFA2T3 NM_005187 611 core-binding factor, hsa-miR- −0.06 0.94 2005, runt domain, alpha 4458 2007, subunit 2; 2009 translocated to, 3 CBL NM_005188 612 Cas-Br-M (murine) hsa-miR- −0.07 0.96 2005, ecotropic retroviral 4500 2007, transforming 2009 sequence CBX2 NM_005189 613 chromobox homolog 2 hsa-miR- −0.15 0.94 2007, 4458 2009 CEBPD NM_005195 614 CCAAT/enhancer hsa-let-7d −0.09 0.86 2009 binding protein (C/EBP), delta ARID3A NM_005224 615 AT rich interactive hsa-miR- −0.11 0.9 2007, domain 3A 4458 2009 (BRIGHT-like) EPHA3 NM_005233 616 EPH receptor A3 hsa-miR- −0.14 0.93 2005, 4500 2007 ERCC4 NM_005236 617 excision repair cross- hsa-miR- −0.1 0.98 2009 complementing 4500 rodent repair deficiency, complementation group 4 GNG5 NM_005274 618 guanine nucleotide hsa-miR- −0.28 0.81 2005, binding protein (G 4458 2007, protein), gamma 5 2009 HAS2 NM_005328 619 hyaluronan synthase 2 hsa-let-7d −0.12 0.87 2005, 2007, 2009 HDLBP NM_005336 620 high density hsa-miR- −0.21 0.98 2007, lipoprotein binding 4458 2009 protein MYCN NM_005378 621 v-myc hsa-let-7i −0.34 0.95 2005, myelocytomatosis 2007, viral related 2009 oncogene, neuroblastoma derived (avian) NUP98 NM_005387 622 nucleoporin 98 kDa hsa-let-7d −0.23 0.85 PRKAB2 NM_005399 623 protein kinase, AMP- hsa-miR- >−0.02 0.89 2009 activated, beta 2 non- 4458 catalytic subunit SLC20A1 NM_005415 624 solute carrier family hsa-miR- −0.31 0.87 2005, 20 (phosphate 4458 2007 transporter), member 1 WNT1 NM_005430 625 wingless-type MMTV hsa-let-7d −0.07 0.88 2005, integration site 2007, family, member 1 2009 GABBR2 NM_005458 626 gamma-aminobutyric hsa-miR- −0.07 0.89 2009 acid (GABA) B 4458 receptor, 2 MED6 NM_005466 627 mediator complex hsa-let-7d −0.14 0.86 2005, subunit 6 2007, 2009 SH2B3 NM_005475 628 SH2B adaptor protein 3 hsa-miR- −0.13 0.94 2007, 4500 2009 INPP5A NM_005539 629 inositol hsa-let-7d −0.1 0.92 2005, polyphosphate-5- 2007, phosphatase, 40 kDa 2009 ISLR NM_005545 630 immunoglobulin hsa-let-7b −0.23 0.86 superfamily containing leucine- rich repeat LIMK2 NM_005569 631 LIM domain kinase 2 hsa-miR-98 −0.14 0.76 MDFI NM_005586 632 MyoD family hsa-miR- −0.11 0.94 2007, inhibitor 4500 2009 ZNF354A NM_005649 633 zinc finger protein hsa-miR- −0.27 0.93 2005, 354A 4500 2007, 2009 SOX13 NM_005686 634 SRY (sex determining hsa-let-7g −0.16 0.9 2005, region Y)-box 13 2007, 2009 ABCC5 NM_005688 635 ATP-binding cassette, hsa-miR- −0.34 0.67 2005, sub-family C 4500 2007, (CFTR/MRP), 2009 member 5 DPP3 NM_005700 636 dipeptidyl-peptidase 3 hsa-miR- −0.35 0.91 2005, 4458 2007, 2009 GIPC1 NM_005716 637 GIPC PDZ domain hsa-miR- −0.26 0.9 2007, containing family, 4458 2009 member 1 TSPAN2 NM_005725 638 tetraspanin 2 hsa-let-7g −0.09 0.94 2009 PLXNC1 NM_005761 639 plexin C1 hsa-miR- −0.33 0.33 4458 AASS NM_005763 640 aminoadipate- hsa-miR- −0.16 <0.1 semialdehyde 4458 synthase FARP1 NM_005766 641 FERM, RhoGEF hsa-miR- −0.16 0.93 2005, (ARHGEF) and 4500 2007, pleckstrin domain 2009 protein 1 (chondrocyte-derived) NME6 NM_005793 642 non-metastatic cells 6, hsa-miR- −0.27 0.94 2005, protein expressed in 4458 2007, (nucleoside- 2009 diphosphate kinase) SPEG NM_005876 643 SPEG complex locus hsa-let-7d −0.11 0.9 2009 DNAJA2 NM_005880 644 DnaJ (Hsp40) hsa-miR- −0.28 0.79 homolog, subfamily 4458 A, member 2 APC2 NM_005883 645 adenomatosis hsa-miR- −0.11 0.83 2009 polyposis coli 2 4458 MEF2D NM_005920 646 myocyte enhancer hsa-miR- >−0.04 0.94 2005, factor 2D 4458 2007, 2009 MAP3K1 NM_005921 647 mitogen-activated hsa-miR- −0.39 0.86 2009 protein kinase kinase 4458 kinase 1 MMP11 NM_005940 648 matrix hsa-let-7d −0.12 0.92 2007, metallopeptidase 11 2009 (stromelysin 3) ALKBH1 NM_006020 649 alkB, alkylation repair hsa-miR- −0.16 0.89 2009 homolog 1 (E. coli) 4500 APBB3 NM_006051 650 amyloid beta (A4) hsa-let-7a −0.41 0.98 2005, precursor protein- 2007, binding, family B, 2009 member 3 DAGLA NM_006133 651 diacylglycerol lipase, hsa-miR- −0.27 0.97 2007, alpha 4458 2009 PRKAA2 NM_006252 652 protein kinase, AMP- hsa-let-7f −0.17 0.93 2009 activated, alpha 2 catalytic subunit RANBP2 NM_006267 653 RAN binding protein 2 hsa-miR- −0.38 0.98 2005, 4458 2007, 2009 DPF2 NM_006268 654 D4, zinc and double hsa-let-7g −0.21 0.94 2005, PHD fingers family 2 2007, 2009 CCL7 NM_006273 655 chemokine (C-C hsa-miR- −0.39 0.9 2009 motif) ligand 7 4458 TNFAIP3 NM_006290 656 tumor necrosis factor, hsa-miR- −0.08 0.92 2009 alpha-induced protein 3 4458 SMC1A NM_006306 657 structural hsa-let-7a −0.46 >0.99 2009 maintenance of chromosomes 1A PCGF3 NM_006315 658 polycomb group ring hsa-let-7a −0.11 0.98 2005, finger 3 2007, 2009 CRTAP NM_006371 659 cartilage associated hsa-miR- −0.11 0.94 2005, protein 4500 2007, 2009 APPBP2 NM_006380 660 amyloid beta hsa-miR- −0.02 0.92 2005, precursor protein 4458 2007 (cytoplasmic tail) binding protein 2 OLFM4 NM_006418 661 olfactomedin 4 hsa-miR- −0.37 <0.1 4500 ARID3B NM_006465 662 AT rich interactive hsa-let-7i −0.72 >0.99 2005, domain 3B 2007, (BRIGHT-like) 2009 IGF2BP3 NM_006547 663 insulin-like growth hsa-let-7a −0.33 0.96 2007, factor 2 mRNA 2009 binding protein 3 CLDN16 NM_006580 664 claudin 16 hsa-miR-98 −0.3 <0.1 MAP3K2 NM_006609 665 mitogen-activated hsa-let-7a −0.1 0.8 protein kinase kinase kinase 2 ARPP19 NM_006628 666 cAMP-regulated hsa-miR-98 −0.09 0.98 2005, phosphoprotein, 2007, 19 kDa 2009 PGRMC1 NM_006667 667 progesterone receptor hsa-miR- −0.46 0.98 2005, membrane component 1 4458 2007, 2009 CYP46A1 NM_006668 668 cytochrome P450, hsa-let-7a −0.17 0.89 2007, family 46, subfamily 2009 A, polypeptide 1 SUB1 NM_006713 669 SUB1 homolog (S. cerevisiae) hsa-miR- −0.36 0.84 4500 BTG2 NM_006763 670 BTG family, member 2 hsa-miR- −0.12 0.89 2005, 4458 2007, 2009 PKIA NM_006823 671 protein kinase hsa-miR- −0.18 0.94 (cAMP-dependent, 4458 catalytic) inhibitor alpha B3GNT1 NM_006876 672 UDP- hsa-miR- −0.34 0.93 2007, GlcNAc:betaGal beta- 4500 2009 1,3-N- acetylglucosaminyltransferase 1 CALM1 NM_006888 673 calmodulin 1 hsa-miR- −0.1 0.93 2005, (phosphorylase 4500 2007, kinase, delta) 2009 PRRX1 NM_006902 674 paired related hsa-miR-98 −0.05 0.95 2007, homeobox 1 2009 RNF5 NM_006913 675 ring finger protein 5 hsa-miR- −0.26 0.64 2005, 4458 2007, 2009 ZNF24 NM_006965 676 zinc finger protein 24 hsa-miR- −0.12 0.94 4500 ADAMTS1 NM_006988 677 ADAM hsa-miR-98 −0.12 0.84 2009 metallopeptidase with thrombospondin type 1 motif, 1 ZNF197 NM_006991 678 zinc finger protein hsa-let-7a −0.38 0.12 197 SLC35D2 NM_007001 679 solute carrier family hsa-let-7d −0.48 0.98 2005, 35, member D2 2007, 2009 CNTRL NM_007018 680 centriolin hsa-miR- −0.42 0.98 2009 4458 ADAMTS8 NM_007037 681 ADAM hsa-miR- −0.4 0.98 2007, metallopeptidase with 4500 2009 thrombospondin type 1 motif, 8 ADAMTS5 NM_007038 682 ADAM hsa-miR- −0.18 0.95 2005, metallopeptidase with 4458 2007, thrombospondin type 2009 1 motif, 5 UTRN NM_007124 683 utrophin hsa-miR- −0.35 0.9 2007, 4458 2009 ZNF81 NM_007137 684 zinc finger protein 81 hsa-miR- −0.07 0.81 4500 TUSC2 NM_007275 685 tumor suppressor hsa-miR- −0.12 0.93 2005, candidate 2 4458 2007, 2009 AP4E1 NM_007347 686 adaptor-related hsa-miR- >−0.02 0.57 protein complex 4, 4458 epsilon 1 subunit NID2 NM_007361 687 nidogen 2 hsa-miR- −0.16 0.92 2005, (osteonidogen) 4500 2007, 2009 BRD3 NM_007371 688 bromodomain hsa-miR- −0.11 0.94 2005, containing 3 4500 2007, 2009 ICOS NM_012092 689 inducible T-cell co- hsa-let-7b −0.24 0.92 2009 stimulator ANGPTL2 NM_012098 690 angiopoietin-like 2 hsa-miR- −0.13 0.93 2005, 4458 2007, 2009 BACE2 NM_012105 691 beta-site APP- hsa-miR- −0.27 0.93 2009 cleaving enzyme 2 4500 FZD4 NM_012193 692 frizzled family hsa-miR- −0.33 0.94 2007, receptor 4 4500 2009 EIF2C1 NM_012199 693 eukaryotic translation hsa-miR- −0.16 0.93 2005, initiation factor 2C, 1 4500 2007, 2009 B3GAT3 NM_012200 694 beta-1,3- hsa-miR- −0.18 0.88 2009 glucuronyltransferase 3 4458 (glucuronosyltransferase I) MGAT4A NM_012214 695 mannosyl (alpha-1,3-)- hsa-miR- −0.29 0.95 2005, glycoprotein beta- 4500 2007, 1,4-N- 2009 acetylgluco saminyltransferase, isozyme A HS2ST1 NM_012262 696 heparan sulfate 2-O- hsa-miR-98 −0.06 0.89 2009 sulfotransferase 1 ESPL1 NM_012291 697 extra spindle pole hsa-miR-98 −0.28 0.57 bodies homolog 1 (S. cerevisiae) PXDN NM_012293 698 peroxidasin homolog hsa-miR- −0.12 >0.99 2007, (Drosophila) 4500 2009 GAB2 NM_012296 699 GRB2-associated hsa-miR- −0.15 0.6 2009 binding protein 2 4458 PLA2G15 NM_012320 700 phospholipase A2, hsa-miR- −0.09 0.92 2005, group XV 4458 2007, 2009 DNAJB9 NM_012328 701 DnaJ (Hsp40) hsa-miR- −0.1 0.91 2005, homolog, subfamily 4500 2007, B, member 9 2009 MYCBP NM_012333 702 c-myc binding protein hsa-miR- −0.08 0.98 2009 4458 MYO1F NM_012335 703 myosin IF hsa-miR- −0.22 0.93 2007, 4500 2009 NNT NM_012343 704 nicotinamide hsa-miR- −0.26 0.87 2009 nucleotide 4458 transhydrogenase PLDN NM_012388 705 pallidin homolog hsa-miR- −0.07 0.94 2005, (mouse) 4500 2007, 2009 CDK14 NM_012395 706 cyclin-dependent hsa-miR- −0.16 0.67 kinase 14 4500 ICMT NM_012405 707 isoprenylcysteine hsa-miR- >−0.03 0.98 2009 carboxyl 4458 methyltransferase RAB3GAP2 NM_012414 708 RAB3 GTPase hsa-let-7d −0.18 0.94 activating protein subunit 2 (non- catalytic) PPARGC1A NM_013261 709 peroxisome hsa-miR- −0.11 0.83 2005, proliferator-activated 4500 2007, receptor gamma, 2009 coactivator 1 alpha EEF2K NM_013302 710 eukaryotic elongation hsa-let-7d −0.17 0.95 2007, factor-2 kinase 2009 SLC30A4 NM_013309 711 solute carrier family hsa-let-7a −0.14 0.94 2005, 30 (zinc transporter), 2007, member 4 2009 HCFC2 NM_013320 712 host cell factor C2 hsa-miR- −0.04 0.91 4500 ATG4B NM_013325 713 ATG4 autophagy hsa-let-7a −0.19 0.79 2009 related 4 homolog B (S. cerevisiae) GPR132 NM_013345 714 G protein-coupled hsa-let-7f −0.21 <0.1 receptor 132 TRHDE NM_013381 715 thyrotropin-releasing hsa-let-7d −0.19 0.99 2005, hormone degrading 2007, enzyme 2009 SLC25A24 NM_013386 716 solute carrier family hsa-miR- −0.24 0.94 2005, 25 (mitochondrial 4458 2007, carrier; phosphate 2009 carrier), member 24 WDR37 NM_014023 717 WD repeat domain 37 hsa-let-7a −0.21 0.99 2005, 2007, 2009 PSORS1C2 NM_014069 718 psoriasis hsa-let-7d −0.15 0.93 susceptibility 1 candidate 2 SCN11A NM_014139 719 sodium channel, hsa-miR- −0.36 0.91 2007, voltage-gated, type 4458 2009 XI, alpha subunit HOXC11 NM_014212 720 homeobox C11 hsa-miR- −0.08 0.94 2005, 4458 2007, 2009 LIMD1 NM_014240 721 LIM domains hsa-let-7b −0.05 0.92 2005, containing 1 2007, 2009 HABP4 NM_014282 722 hyaluronan binding hsa-miR- −0.18 0.94 2009 protein 4 4458 TGDS NM_014305 723 TDP-glucose 4,6- hsa-miR- −0.24 0.95 2009 dehydratase 4500 SMUG1 NM_014311 724 single-strand- hsa-let-7d −0.35 0.92 2009 selective monofunctional uracil-DNA glycosylase 1 CACNG4 NM_014405 725 calcium channel, hsa-miR- −0.17 0.84 2005, voltage-dependent, 4458 2007, gamma subunit 4 2009 KIAA1274 NM_014431 726 KIAA1274 hsa-miR-98 −0.38 0.98 2009 ZKSCAN5 NM_014569 727 zinc finger with hsa-miR- −0.1 0.77 KRAB and SCAN 4458 domains 5 ERO1L NM_014584 728 ERO1-like (S. cerevisiae) hsa-miR- −0.18 0.88 2009 4500 SOCS7 NM_014598 729 suppressor of hsa-miR- >−0.02 0.92 cytokine signaling 7 4458 UBXN4 NM_014607 730 UBX domain protein 4 hsa-let-7a −0.15 0.89 2005, 2007, 2009 RALGPS1 NM_014636 731 Ral GEF with PH hsa-miR- −0.15 0.94 2005, domain and SH3 4500 2007, binding motif 1 2009 TTLL4 NM_014640 732 tubulin tyrosine hsa-let-7d −0.56 >0.99 2003, ligase-like family, 2005, member 4 2007, 2009 ZNF516 NM_014643 733 zinc finger protein hsa-miR- −0.04 0.95 2009 516 4500 GREB1 NM_014668 734 growth regulation by hsa-miR- −0.17 0.88 2009 estrogen in breast 4500 cancer 1 ULK2 NM_014683 735 unc-51-like kinase 2 hsa-miR-98 −0.14 0.95 2005, (C. elegans) 2007, 2009 SEC14L5 NM_014692 736 SEC14-like 5 (S. cerevisiae) hsa-let-7d −0.14 0.98 2009 TBKBP1 NM_014726 737 TBK1 binding protein 1 hsa-miR- −0.36 0.97 2007, 4500 2009 RIMS3 NM_014747 738 regulating synaptic hsa-miR- >−0.01 0.92 2009 membrane exocytosis 3 4458 TSC22D2 NM_014779 739 TSC22 domain hsa-miR- −0.16 0.87 2005, family, member 2 4458 2007, 2009 LRIG2 NM_014813 740 leucine-rich repeats hsa-let-7d −0.48 0.95 2005, and immunoglobulin- 2007, like domains 2 2009 ZBTB39 NM_014830 741 zinc finger and BTB hsa-miR- −0.04 0.98 2007, domain containing 39 4458 2009 TRANK1 NM_014831 742 tetratricopeptide hsa-let-7b −0.3 0.85 2009 repeat and ankyrin repeat containing 1 TECPR2 NM_014844 743 tectonin beta- hsa-let-7d −0.13 0.94 2005, propeller repeat 2007, containing 2 2009 ZBTB5 NM_014872 744 zinc finger and BTB hsa-let-7f −0.23 0.92 2005, domain containing 5 2007, 2009 LPGAT1 NM_014873 745 lysophosphatidylglycerol hsa-let-7g −0.34 >0.99 2005, acyltransferase 1 2007, 2009 HELZ NM_014877 746 helicase with zinc hsa-let-7d −0.28 0.9 finger RNF44 NM_014901 747 ring finger protein 44 hsa-let-7i −0.14 0.94 2005, 2007, 2009 AAK1 NM_014911 748 AP2 associated kinase 1 hsa-miR- >−0.03 0.92 2007, 4458 2009 DZIP1 NM_014934 749 DAZ interacting hsa-miR- −0.11 0.94 2005, protein 1 4500 2007, 2009 MLXIP NM_014938 750 MLX interacting hsa-miR- −0.11 0.8 protein 4458 BAHD1 NM_014952 751 bromo adjacent hsa-miR- −0.05 0.89 2005, homology domain 4458 2007, containing 1 2009 CEP164 NM_014956 752 centrosomal protein hsa-miR- −0.08 0.93 2005, 164 kDa 4458 2007, 2009 RUFY3 NM_014961 753 RUN and FYVE hsa-let-7f −0.13 0.93 2007, domain containing 3 2009 BTBD3 NM_014962 754 BTB (POZ) domain hsa-let-7c −0.19 0.92 2005, containing 3 2007, 2009 MON2 NM_015026 755 MON2 homolog (S. cerevisiae) hsa-miR- −0.09 0.94 2007, 4458 2009 NMNAT2 NM_015039 756 nicotinamide hsa-miR- >−0.01 0.72 nucleotide 4458 adenylyltransferase 2 RRP1B NM_015056 757 ribosomal RNA hsa-miR- −0.09 0.93 2007, processing 1 homolog 4458 2009 B (S. cerevisiae) SLC8A2 NM_015063 758 solute carrier family 8 hsa-miR- −0.07 0.91 2005, (sodium/calcium 4458 2007, exchanger), member 2 2009 DDN NM_015086 759 dendrin hsa-miR- −0.18 0.92 2009 4500 TAB2 NM_015093 760 TGF-beta activated hsa-miR- −0.16 0.83 2005, kinase 1/MAP3K7 4500 2007, binding protein 2 2009 HIC2 NM_015094 761 hypermethylated in hsa-miR- −0.45 >0.99 2003, cancer 2 4458 2005, 2007, 2009 PLXND1 NM_015103 762 plexin D1 hsa-miR- −0.35 0.98 2007, 4500 2009 ZC3H3 NM_015117 763 zinc finger CCCH- hsa-let-7d −0.3 0.98 2007, type containing 3 2009 FRMD4B NM_015123 764 FERM domain hsa-miR- −0.31 0.86 2009 containing 4B 4500 DTX4 NM_015177 765 deltex homolog 4 hsa-miR- −0.06 0.98 2009 (Drosophila) 4500 OTUD3 NM_015207 766 OTU domain hsa-miR- >−0.01 0.82 2009 containing 3 4458 KHNYN NM_015299 767 KH and NYN domain hsa-let-7f −0.44 0.93 containing USP24 NM_015306 768 ubiquitin specific hsa-miR- −0.26 0.93 2009 peptidase 24 4458 FAM189A1 NM_015307 769 family with sequence hsa-miR- −0.19 0.94 2009 similarity 189, 4458 member A1 LEPROTL1 NM_015344 770 leptin receptor hsa-let-7d −0.09 0.82 2005, overlapping 2007 transcript-like 1 ZFYVE26 NM_015346 771 zinc finger, FYVE hsa-miR- −0.38 0.98 2005, domain containing 26 4458 2007, 2009 PARM1 NM_015393 772 prostate androgen- hsa-miR- −0.24 0.97 2009 regulated mucin-like 4458 protein 1 ARMC8 NM_015396 773 armadillo repeat hsa-miR- −0.1 0.87 containing 8 4500 AHCTF1 NM_015446 774 AT hook containing hsa-miR- −0.38 0.4 2007, transcription factor 1 4458 2009 MYRIP NM_015460 775 myosin VIIA and Rab hsa-miR- −0.11 0.85 2005, interacting protein 4458 2007, 2009 SLC22A23 NM_015482 776 solute carrier family hsa-miR- −0.27 0.98 22, member 23 4458 PNKD NM_015488 777 paroxysmal hsa-miR- −0.14 0.76 2007, nonkinesigenic 4458 2009 dyskinesia SEC31B NM_015490 778 SEC31 homolog B (S. cerevisiae) hsa-miR- −0.15 0.82 2009 4458 C15orf39 NM_015492 779 chromosome 15 open hsa-let-7a −0.31 0.93 2009 reading frame 39 LRIG1 NM_015541 780 leucine-rich repeats hsa-miR- N/A 0.95 2005, and immunoglobulin- 4458 2007, like domains 1 2009 OSBPL3 NM_015550 781 oxysterol binding hsa-miR- −0.2 0.95 2005, protein-like 3 4458 2007, 2009 LTN1 NM_015565 782 listerin E3 ubiquitin hsa-let-7d −0.22 0.93 2005, protein ligase 1 2007, 2009 PLA2G3 NM_015715 783 phospholipase A2, hsa-let-7a −0.35 0.91 2009 group III DCAF8 NM_015726 784 DDB1 and CUL4 hsa-miR- −0.1 0.66 associated factor 8 4500 WARS2 NM_015836 785 tryptophanyl tRNA hsa-miR- −0.3 <0.1 2009 synthetase 2, 4458 mitochondrial MBTPS2 NM_015884 786 membrane-bound hsa-miR- −0.06 0.86 transcription factor 4458 peptidase, site 2 HOOK1 NM_015888 787 hook homolog 1 hsa-miR- −0.12 0.94 2007, (Drosophila) 4458 2009 TAF9B NM_015975 788 TAF9B RNA hsa-let-7a −0.3 0.98 2009 polymerase II, TATA box binding protein (TBP)-associated factor, 31 kDa GOLT1B NM_016072 789 golgi transport 1B hsa-miR- −0.18 0.98 2005, 4500 2007, 2009 CERCAM NM_016174 790 cerebral endothelial hsa-let-7d −0.15 0.93 2007, cell adhesion 2009 molecule VGLL3 NM_016206 791 vestigial like 3 hsa-miR- −0.11 0.94 2009 (Drosophila) 4458 NLK NM_016231 792 nemo-like kinase hsa-miR- −0.14 0.87 2005, 4500 2007, 2009 SCARA3 NM_016240 793 scavenger receptor hsa-miR- −0.03 0.77 class A, member 3 4500 IMPG2 NM_016247 794 interphotoreceptor hsa-let-7i −0.31 0.95 matrix proteoglycan 2 TOB2 NM_016272 795 transducer of ERBB2, 2 hsa-miR- >−0.02 0.94 2005, 4458 2007, 2009 PLEKHO1 NM_016274 796 pleckstrin homology hsa-miR- −0.2 0.79 2007, domain containing, 4458 2009 family O member 1 ANKFY1 NM_016376 797 ankyrin repeat and hsa-miR- >−0.03 0.98 2005, FYVE domain 4458 2007, containing 1 2009 LUC7L3 NM_016424 798 LUC7-like 3 (S. cerevisiae) hsa-miR- −0.05 0.85 2005, 4500 2007, 2009 RAB8B NM_016530 799 RAB8B, member hsa-let-7f −0.07 0.92 2007 RAS oncogene family GCNT4 NM_016591 800 glucosaminyl (N- hsa-miR- −0.34 0.91 2007, acetyl) transferase 4, 4500 2009 core 2 UFM1 NM_016617 801 ubiquitin-fold hsa-miR- −0.36 0.63 2009 modifier 1 4458 ZNF644 NM_016620 802 zinc finger protein hsa-miR- −0.28 0.97 2005, 644 4458 2007, 2009 FZD3 NM_017412 803 frizzled family hsa-miR-98 −0.2 >0.99 receptor 3 RBM38 NM_017495 804 RNA binding motif hsa-miR- −0.25 0.98 2007, protein 38 4458 2009 STAB2 NM_017564 805 stabilin 2 hsa-miR- −0.13 0.9 2005, 4500 2007, 2009 KIF21B NM_017596 806 kinesin family hsa-miR- >−0.03 0.95 2007, member 21B 4458 2009 EIF2C4 NM_017629 807 eukaryotic translation hsa-let-7d −0.17 0.95 2005, initiation factor 2C, 4 2007, 2009 BNC2 NM_017637 808 basonuclin 2 hsa-let-7g −0.03 0.88 2005, 2007, 2009 KLHL24 NM_017644 809 kelch-like 24 hsa-miR- >−0.01 0.87 2007, (Drosophila) 4458 2009 GDAP2 NM_017686 810 ganglioside induced hsa-let-7d −0.33 0.97 2009 differentiation associated protein 2 FBXL12 NM_017703 811 F-box and leucine- hsa-miR- −0.32 0.92 2007, rich repeat protein 12 4458 2009 ANKRD49 NM_017704 812 ankyrin repeat hsa-miR- −0.25 0.9 2007, domain 49 4500 2009 UHRF1BP1 NM_017754 813 UHRF1 binding hsa-miR- −0.03 0.85 protein 1 4500 INO80D NM_017759 814 INO80 complex hsa-miR- −0.12 0.91 2005, subunit D 4500 2007, 2009 CHD7 NM_017780 815 chromodomain hsa-miR- −0.07 0.86 2005, helicase DNA binding 4500 2007, protein 7 2009 SEMA4C NM_017789 816 sema domain, hsa-let-7i −0.32 0.98 2005, immunoglobulin 2007, domain (Ig), 2009 transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4C CMTM6 NM_017801 817 CKLF-like MARVEL hsa-let-7c −0.16 <0.1 transmembrane domain containing 6 HIF1AN NM_017902 818 hypoxia inducible hsa-miR- −0.47 0.94 2009 factor 1, alpha subunit 4500 inhibitor STX17 NM_017919 819 syntaxin 17 hsa-miR- −0.16 0.97 2005, 4500 2007, 2009 USP47 NM_017944 820 ubiquitin specific hsa-let-7d −0.14 0.94 2007, peptidase 47 2009 PDPR NM_017990 821 pyruvate hsa-miR- −0.3 0.95 2005, dehydrogenase 4500 2007, phosphatase 2009 regulatory subunit C9orf40 NM_017998 822 chromosome 9 open hsa-let-7f −0.55 0.76 2009 reading frame 40 XKR8 NM_018053 823 XK, Kell blood group hsa-miR- −0.49 0.98 2007, complex subunit- 4458 2009 related family, member 8 PRPF38B NM_018061 824 PRP38 pre-mRNA hsa-miR- −0.32 0.26 2007, processing factor 38 4458 2009 (yeast) domain containing B IPO9 NM_018085 825 importin 9 hsa-miR- −0.06 0.78 2009 4500 FIGN NM_018086 826 fidgetin hsa-let-7d −0.56 >0.99 2007, 2009 CDCA8 NM_018101 827 cell division cycle hsa-miR- −0.17 0.94 2009 associated 8 4458 FAM178A NM_018121 828 family with sequence hsa-miR-98 −0.24 0.98 2003, similarity 178, 2005, member A 2007, 2009 LRRC20 NM_018205 829 leucine rich repeat hsa-miR- −0.04 0.87 2009 containing 20 4458 ETNK2 NM_018208 830 ethanolamine kinase 2 hsa-miR- −0.14 0.93 2005, 4458 2007, 2009 TMEM143 NM_018273 831 transmembrane hsa-miR- −0.23 0.9 2009 protein 143 4500 BRF2 NM_018310 832 BRF2, subunit of hsa-miR- −0.43 <0.1 2009 RNA polymerase III 4500 transcription initiation factor, BRF1-like DDX19A NM_018332 833 DEAD (Asp-Glu-Ala- hsa-miR- −0.47 0.94 2007, As) box polypeptide 4500 2009 19A FGD6 NM_018351 834 FYVE, RhoGEF and hsa-miR- −0.32 0.99 2009 PH domain 4458 containing 6 ACER3 NM_018367 835 alkaline ceramidase 3 hsa-let-7d −0.2 0.93 SYNJ2BP NM_018373 836 synaptojanin 2 hsa-miR- −0.11 0.85 binding protein 4500 PAG1 NM_018440 837 phosphoprotein hsa-miR- −0.3 0.98 2009 associated with 4458 glycosphingolipid microdomains 1 ACTR10 NM_018477 838 actin-related protein hsa-let-7f −0.34 0.75 2009 10 homolog (S. cerevisiae) LGR4 NM_018490 839 leucine-rich repeat hsa-miR- −0.2 0.92 2005, containing G protein- 4500 2007, coupled receptor 4 2009 YOD1 NM_018566 840 YOD1 OTU hsa-miR- −0.57 >0.99 2007, deubiquinating 4500 2009 enzyme 1 homolog (S. cerevisiae) SLC16A10 NM_018593 841 solute carrier family hsa-miR- −0.14 0.86 2009 16, member 10 4500 (aromatic amino acid transporter) ETNK1 NM_018638 842 ethanolamine kinase 1 hsa-miR- −0.05 0.92 2007, 4500 2009 B3GAT1 NM_018644 843 beta-1,3- hsa-let-7d −0.02 0.9 2009 glucuronyltransferase 1 (glucuronosyltransferase P) BIN3 NM_018688 844 bridging integrator 3 hsa-let-7g −0.22 0.92 2005, 2007, 2009 YIPF1 NM_018982 845 Yip1 domain family, hsa-let-7d −0.18 0.71 member 1 SSH1 NM_018984 846 slingshot homolog 1 hsa-let-7a −0.17 0.95 2005, (Drosophila) 2007, 2009 SMCR7L NM_019008 847 Smith-Magenis hsa-let-7f −0.08 0.94 2007, syndrome 2009 chromosome region, candidate 7-like CCDC93 NM_019044 848 coiled-coil domain hsa-miR- −0.07 0.62 2009 containing 93 4458 CRCT1 NM_019060 849 cysteine-rich C- hsa-miR- −0.28 0.92 2009 terminal 1 4500 CCDC76 NM_019083 850 coiled-coil domain hsa-let-7f −0.38 0.72 containing 76 UBFD1 NM_019116 851 ubiquitin family hsa-miR- −0.1 0.87 2007, domain containing 1 4458 2009 TMEM234 NM_019118 852 transmembrane hsa-let-7a −0.37 0.92 2009 protein 234 RNF20 NM_019592 853 ring finger protein 20 hsa-let-7g −0.27 0.7 2005, 2007 GPCPD1 NM_019593 854 glycerophosphocholine hsa-miR- −0.42 >0.99 2007, phosphodiesterase 4500 2009 GDE1 homolog (S. cerevisiae) ABCB9 NM_019624 855 ATP-binding cassette, hsa-miR-98 −0.3 0.95 2005, sub-family B 2007, (MDR/TAP), member 9 2009 UGGT1 NM_020120 856 UDP-glucose hsa-miR- −0.22 0.98 2007, glycoprotein 4458 2009 glucosyltransferase 1 KCMF1 NM_020122 857 potassium channel hsa-let-7g −0.02 0.93 2009 modulatory factor 1 C1GALT1 NM_020156 858 core 1 synthase, hsa-miR-98 −0.07 0.98 glycoprotein-N- acetylgalactosamine 3-beta- galactosyltransferase, 1 SLC12A9 NM_020246 859 solute carrier family hsa-miR- −0.29 0.98 2009 12 4458 (potassium/chloride transporters), member 9 MNT NM_020310 860 MAX binding protein hsa-let-7d −0.02 0.93 2005, 2007, 2009 VANGL2 NM_020335 861 vang-like 2 (van hsa-miR- −0.06 >0.99 2007, gogh, Drosophila) 4458 2009 KIAA1244 NM_020340 862 KIAA1244 hsa-miR- >−0.02 0.79 4458 ENTPD7 NM_020354 863 ectonucleoside hsa-let-7d −0.17 0.94 triphosphate diphosphohydrolase 7 AVEN NM_020371 864 apoptosis, caspase hsa-let-7i −0.22 0.59 activation inhibitor SCYL3 NM_020423 865 SCY1-like 3 (S. cerevisiae) hsa-let-7f −0.18 0.93 2005, 2007, 2009 ASPHD2 NM_020437 866 aspartate beta- hsa-miR- −0.02 0.8 hydroxylase domain 4458 containing 2 GALNT1 NM_020474 867 UDP-N-acetyl-alpha- hsa-miR- −0.47 >0.99 2005, D- 4500 2007, galactosamine:polypeptide 2009 N- acetylgalactosaminyltransferase 1 (GalNAc-T1) MRS2 NM_020662 868 MRS2 magnesium hsa-let-7f −0.48 0.91 2009 homeostasis factor homolog (S. cerevisiae) RAB22A NM_020673 869 RAB22A, member hsa-miR- −0.15 0.88 2009 RAS oncogene family 4500 ZNF512B NM_020713 870 zinc finger protein hsa-miR- −0.31 >0.99 2007, 512B 4458 2009 PLEKHH1 NM_020715 871 pleckstrin homology hsa-miR- −0.2 0.93 2007, domain containing, 4500 2009 family H (with MyTH4 domain) member 1 NLN NM_020726 872 neurolysin hsa-miR- −0.1 0.79 (metallopeptidase M3 4458 family) INTS2 NM_020748 873 integrator complex hsa-let-7a −0.3 0.84 2007, subunit 2 2009 STARD9 NM_020759 874 StAR-related lipid hsa-miR- −0.7 0.79 transfer (START) 4458 domain containing 9 SRGAP1 NM_020762 875 SLIT-ROBO Rho hsa-miR- −0.08 0.73 GTPase activating 4458 protein 1 CASKIN1 NM_020764 876 CASK interacting hsa-let-7i −0.1 0.89 2005, protein 1 2007, 2009 KCTD16 NM_020768 877 potassium channel hsa-miR- −0.19 0.87 2009 tetramerisation 4458 domain containing 16 RGAG1 NM_020769 878 retrotransposon gag hsa-let-7f −0.14 0.79 2005, domain containing 1 2007 MIB1 NM_020774 879 mindbomb homolog 1 hsa-let-7f −0.15 >0.99 2007, (Drosophila) 2009 ALPK3 NM_020778 880 alpha-kinase 3 hsa-miR- >−0.02 0.84 2009 4458 PDP2 NM_020786 881 pyruvate hsa-let-7b −0.18 0.92 2009 dehyrogenase phosphatase catalytic subunit 2 TAOK1 NM_020791 882 TAO kinase 1 hsa-let-7g −0.07 0.91 ARHGAP20 NM_020809 883 Rho GTPase hsa-let-7a −0.11 0.93 2005, activating protein 20 2007, 2009 KIAA1467 NM_020853 884 KIAA1467 hsa-miR- −0.15 0.83 2009 4458 ZSWIM5 NM_020883 885 zinc finger, SWIM- hsa-miR- −0.29 0.97 2009 type containing 5 4458 PLXNA4 NM_020911 886 plexin A4 hsa-miR- −0.15 >0.99 2009 4500 SLC7A14 NM_020949 887 solute carrier family 7 hsa-let-7d −0.07 0.94 (orphan transporter), member 14 IGDCC4 NM_020962 888 immunoglobulin hsa-let-7a −0.24 0.98 2005, superfamily, DCC 2007, subclass, member 4 2009 SPTBN4 NM_020971 889 spectrin, beta, non- hsa-miR- −0.07 0.87 2007, erythrocytic 4 4458 2009 XK NM_021083 890 X-linked Kx blood hsa-miR- −0.29 0.93 2009 group (McLeod 4458 syndrome) MTMR3 NM_021090 891 myotubularin related hsa-let-7a −0.05 0.88 2009 protein 3 SLC5A6 NM_021095 892 solute carrier family 5 hsa-let-7f −0.21 0.93 2007, (sodium-dependent 2009 vitamin transporter), member 6 COL14A1 NM_021110 893 collagen, type XIV, hsa-miR- −0.3 0.71 2007 alpha 1 4500 PMAIP1 NM_021127 894 phorbol-12-myristate- hsa-miR- −0.17 0.9 2009 13-acetate-induced 4500 protein 1 FAM108C1 NM_021214 895 family with sequence hsa-miR-98 −0.2 0.72 similarity 108, member C1 RRAGD NM_021244 896 Ras-related GTP hsa-miR- −0.1 0.93 binding D 4500 CDH22 NM_021248 897 cadherin 22, type 2 hsa-miR- −0.23 0.88 4500 SNX6 NM_021249 898 sorting nexin 6 hsa-let-7c −0.38 0.98 2009 SENP2 NM_021627 899 SUMO1/sentrin/SMT hsa-miR- −0.17 0.8 2005, 3 specific peptidase 2 4458 2007, 2009 TRIB2 NM_021643 900 tribbles homolog 2 hsa-miR- −0.11 0.84 2005, (Drosophila) 4458 2007, 2009 SPCS3 NM_021928 901 signal peptidase hsa-miR- −0.06 0.81 complex subunit 3 4458 homolog (S. cerevisiae) FKBP10 NM_021939 902 FK506 binding hsa-let-7d −0.08 0.65 protein 10, 65 kDa TIA1 NM_022037 903 TIA1 cytotoxic hsa-let-7f −0.12 0.93 granule-associated RNA binding protein GAN NM_022041 904 gigaxonin hsa-miR- −0.26 0.98 2005, 4500 2007, 2009 CERS2 NM_022075 905 ceramide synthase 2 hsa-let-7c −0.11 0.69 PRSS22 NM_022119 906 protease, serine, 22 hsa-miR-98 −0.2 0.84 SNX16 NM_022133 907 sorting nexin 16 hsa-miR- −0.23 0.94 2005, 4500 2007, 2009 XYLT1 NM_022166 908 xylosyltransferase I hsa-miR- >−0.03 0.99 2007, 4458 2009 DNAJC1 NM_022365 909 DnaJ (Hsp40) hsa-let-7d −0.21 0.85 2005, homolog, subfamily 2007, C, member 1 2009 NSD1 NM_022455 910 nuclear receptor hsa-miR- −0.12 0.76 binding SET domain 4458 protein 1 HIF3A NM_022462 911 hypoxia inducible hsa-let-7b −0.35 >0.99 2009 factor 3, alpha subunit ZMAT3 NM_022470 912 zinc finger, matrin- hsa-miR- >−0.01 0.73 type 3 4458 TTC31 NM_022492 913 tetratricopeptide hsa-miR- −0.36 0.87 2009 repeat domain 31 4458 MESDC1 NM_022566 914 mesoderm hsa-miR- −0.15 0.8 2005, development 4500 2007, candidate 1 2009 ELOVL4 NM_022726 915 ELOVL fatty acid hsa-miR- −0.16 0.94 2005, elongase 4 4500 2007, 2009 FAM160B2 NM_022749 916 family with sequence hsa-miR- −0.06 0.92 2005, similarity 160, 4458 2007, member B2 2009 AEN NM_022767 917 apoptosis enhancing hsa-miR- −0.31 0.93 2009 nuclease 4458 RNF38 NM_022781 918 ring finger protein 38 hsa-let-7g −0.13 0.7 2005, 2007, 2009 ANKRA2 NM_023039 919 ankyrin repeat, family hsa-miR- −0.19 0.84 A (RFXANK-like), 2 4458 ZSWIM4 NM_023072 920 zinc finger, SWIM- hsa-miR- −0.03 0.79 2007 type containing 4 4458 OTUB2 NM_023112 921 OTU domain, hsa-miR- −0.09 0.65 ubiquitin aldehyde 4458 binding 2 LRFN4 NM_024036 922 leucine rich repeat hsa-miR- −0.12 0.89 2007, and fibronectin type 4458 2009 III domain containing 4 GNPTAB NM_024312 923 N-acetylglucosamine- hsa-miR- −0.48 0.95 2007, 1-phosphate 4500 2009 transferase, alpha and beta subunits EFHD2 NM_024329 924 EF-hand domain hsa-let-7f −0.19 0.97 2005, family, member D2 2007, 2009 HOXD1 NM_024501 925 homeobox D1 hsa-miR- −0.25 0.93 2005, 4500 2007, 2009 ADIPOR2 NM_024551 926 adiponectin receptor 2 hsa-let-7f −0.16 0.94 2005, 2007, 2009 CCNJL NM_024565 927 cyclin J-like hsa-let-7f −0.12 0.89 2009 SRD5A3 NM_024592 928 steroid 5 alpha- hsa-let-7a −0.4 0.84 reductase 3 THAP9 NM_024672 929 THAP domain hsa-miR- −0.47 0.9 containing 9 4458 LIN28A NM_024674 930 lin-28 homolog A (C. elegans) hsa-let-7i −0.25 0.98 2005, 2007, 2009 KCTD17 NM_024681 931 potassium channel hsa-miR- −0.24 0.98 2007, tetramerisation 4458 2009 domain containing 17 C15orf29 NM_024713 932 chromosome 15 open hsa-miR- −0.18 0.94 2005, reading frame 29 4458 2007, 2009 MOBKL2B NM_024761 933 MOB1, Mps One hsa-miR- >−0.03 0.93 2009 Binder kinase 4458 activator-like 2B (yeast) ATP8B4 NM_024837 934 ATPase, class I, type hsa-let-7a −0.25 0.94 2009 8B, member 4 EIF2C3 NM_024852 935 eukaryotic translation hsa-let-7f −0.13 0.83 2005, initiation factor 2C, 3 2007, 2009 L2HGDH NM_024884 936 L-2-hydroxyglutarate hsa-let-7a −0.05 0.98 2009 dehydrogenase C7orf58 NM_024913 937 chromosome 7 open hsa-let-7g −0.14 0.92 2005, reading frame 58 2007, 2009 PHC3 NM_024947 938 polyhomeotic hsa-let-7b −0.05 0.84 2009 homolog 3 (Drosophila) CEP135 NM_025009 939 centrosomal protein hsa-let-7b −0.34 0.95 2009 135 kDa ARHGEF15 NM_025014 940 Rho guanine hsa-miR- −0.23 0.94 2005, nucleotide exchange 4500 2007, factor (GEF) 15 2009 VCPIP1 NM_025054 941 valosin containing hsa-miR- >−0.01 0.76 2005, protein (p97)/p47 4458 2007 complex interacting protein 1 FRAS1 NM_025074 942 Fraser syndrome 1 hsa-let-7b −0.42 0.95 2005, 2007, 2009 NYNRIN NM_025081 943 NYN domain and hsa-let-7d −0.32 >0.99 2007, retroviral integrase 2009 containing CHD9 NM_025134 944 chromodomain hsa-let-7a −0.07 0.74 2005, helicase DNA binding 2007 protein 9 KIAA1539 NM_025182 945 KIAA1539 hsa-miR- −0.25 0.92 2005, 4458 2007, 2009 EDEM3 NM_025191 946 ER degradation hsa-miR- −0.21 0.98 2007, enhancer, 4500 2009 mannosidase alpha- like 3 TRIB1 NM_025195 947 tribbles homolog 1 hsa-miR- −0.1 0.92 2005, (Drosophila) 4500 2007, 2009 TRABD NM_025204 948 TraB domain hsa-miR- −0.22 0.73 2007, containing 4458 2009 MED28 NM_025205 949 mediator complex hsa-miR- −0.45 0.32 subunit 28 4500 SOST NM_025237 950 sclerostin hsa-miR- −0.04 0.87 2009 4500 LIMD2 NM_030576 951 LIM domain hsa-let-7i −0.38 0.95 2007, containing 2 2009 CPEB4 NM_030627 952 cytoplasmic hsa-let-7d −0.08 0.96 2005, polyadenylation 2007, element binding 2009 protein 4 DUSP16 NM_030640 953 dual specificity hsa-let-7d −0.19 0.97 2005, phosphatase 16 2007, 2009 C1orf21 NM_030806 954 chromosome 1 open hsa-let-7g −0.03 0.77 reading frame 21 LBH NM_030915 955 limb bud and heart hsa-let-7g −0.07 0.92 2005, development homolog 2007, (mouse) 2009 FAM103A1 NM_031452 956 family with sequence hsa-miR- −0.42 0.87 2009 similarity 103, 4458 member A1 SLC25A18 NM_031481 957 solute carrier family hsa-miR- −0.34 0.94 2005, 25 (mitochondrial 4458 2007, carrier), member 18 2009 KCTD10 NM_031954 958 potassium channel hsa-miR- >−0.02 0.86 2009 tetramerisation 4458 domain containing 10 STARD3NL NM_032016 959 STARD3 N-terminal hsa-miR- −0.15 0.91 2005, like 4458 2007, 2009 STK40 NM_032017 960 serine/threonine hsa-miR- −0.25 0.95 2007, kinase 40 4458 2009 UTP15 NM_032175 961 UTP15, U3 small hsa-let-7b −0.16 0.79 2009 nucleolar ribonucleoprotein, homolog (S. cerevisiae) LOXL4 NM_032211 962 lysyl oxidase-like 4 hsa-let-7a −0.13 0.94 2005, 2007, 2009 DDI2 NM_032341 963 DNA-damage hsa-miR- −0.46 0.98 2007, inducible 1 homolog 4500 2009 2 (S. cerevisiae) MEGF11 NM_032445 964 multiple EGF-like- hsa-miR- −0.05 0.88 2009 domains 11 4500 DOT1L NM_032482 965 DOT1-like, histone hsa-miR- N/A 0.99 2005, H3 methyltransferase 4458 2007, (S. cerevisiae) 2009 C6orf168 NM_032511 966 chromosome 6 open hsa-miR- −0.22 0.95 2009 reading frame 168 4458 PARD6B NM_032521 967 par-6 partitioning hsa-let-7a −0.29 0.95 2007, defective 6 homolog 2009 beta (C. elegans) USP38 NM_032557 968 ubiquitin specific hsa-miR- −0.33 0.85 2005, peptidase 38 4500 2007, 2009 USP32 NM_032582 969 ubiquitin specific hsa-let-7a −0.2 0.93 2005, peptidase 32 2007, 2009 LOXL3 NM_032603 970 lysyl oxidase-like 3 hsa-miR- −0.1 0.79 2005, 4458 2007, 2009 FOXP1 NM_032682 971 forkhead box P1 hsa-let-7g −0.04 0.85 2009 SFT2D3 NM_032740 972 SFT2 domain hsa-let-7a −0.34 <0.1 2009 containing 3 LINGO1 NM_032808 973 leucine rich repeat hsa-let-7d −0.3 0.89 2009 and Ig domain containing 1 ZNF341 NM_032819 974 zinc finger protein hsa-let-7a −0.42 <0.1 341 PPP1R15B NM_032833 975 protein phosphatase 1, hsa-let-7c −0.44 >0.99 2005, regulatory (inhibitor) 2007, subunit 15B 2009 CGNL1 NM_032866 976 cingulin-like 1 hsa-miR- −0.2 0.94 2005, 4458 2007, 2009 RAB11FIP4 NM_032932 977 RAB11 family hsa-let-7d −0.27 >0.99 2003, interacting protein 4 2005, (class II) 2007, 2009 C5orf62 NM_032947 978 chromosome 5 open hsa-let-7d −0.38 0.92 2007, reading frame 62 2009 ZCCHC3 NM_033089 979 zinc finger, CCHC hsa-miR- −0.16 0.93 2007, domain containing 3 4458 2009 NKD1 NM_033119 980 naked cuticle hsa-let-7a −0.2 0.95 2005, homolog 1 2007, (Drosophila) 2009 SCRT2 NM_033129 981 scratch homolog 2, hsa-miR- −0.05 0.88 2005, zinc finger protein 4458 2007, (Drosophila) 2009 SURF4 NM_033161 982 surfeit 4 hsa-let-7a −0.02 0.87 2005, 2007, 2009 PURB NM_033224 983 purine-rich element hsa-miR- −0.03 0.87 2009 binding protein B 4458 RASL10B NM_033315 984 RAS-like, family 10, hsa-miR- −0.06 0.94 2005, member B 4458 2007, 2009 C20orf54 NM_033409 985 chromosome 20 open hsa-miR- −0.3 <0.1 reading frame 54 4458 FAM125B NM_033446 986 family with sequence hsa-miR- >−0.01 0.77 2007, similarity 125, 4458 2009 member B TSPYL5 NM_033512 987 TSPY-like 5 hsa-miR- −0.24 0.58 4458 TRIM41 NM_033549 988 tripartite motif hsa-let-7f −0.22 0.92 containing 41 STARD13 NM_052851 989 StAR-related lipid hsa-let-7g −0.4 >0.99 2005, transfer (START) 2007, domain containing 13 2009 VPS26B NM_052875 990 vacuolar protein hsa-miR- −0.15 0.9 2009 sorting 26 homolog B 4500 (S. pombe) EGLN2 NM_053046 991 egl nine homolog 2 hsa-miR- −0.16 0.93 2005, (C. elegans) 4500 2007, 2009 CCND1 NM_053056 992 cyclin D1 hsa-let-7b −0.12 0.99 2005, 2007, 2009 GALNTL2 NM_054110 993 UDP-N-acetyl-alpha- hsa-miR- −0.2 0.94 2005, D- 4500 2007, galactosamine:polypeptide 2009 N- acetylgalactosaminyltransferase- like 2 C20orf112 NM_080616 994 chromosome 20 open hsa-let-7b −0.22 0.97 reading frame 112 TMEM41A NM_080652 995 transmembrane hsa-miR- −0.13 0.94 protein 41A 4458 ADAMTS14 NM_080722 996 ADAM hsa-miR- −0.18 0.93 2007, metallopeptidase with 4458 2009 thrombospondin type 1 motif, 14 ZNF280B NM_080764 997 zinc finger protein hsa-let-7d −0.34 0.98 2007, 280B 2009 SOCS4 NM_080867 998 suppressor of hsa-miR- −0.15 0.91 2005, cytokine signaling 4 4500 2007, 2009 KLHL6 NM_130446 999 kelch-like 6 hsa-let-7d −0.32 0.95 2007, (Drosophila) 2009 TSPAN18 NM_130783 1000 tetraspanin 18 hsa-miR- −0.08 0.94 4500 UNC5A NM_133369 1001 unc-5 homolog A (C. elegans) hsa-let-7d −0.12 0.9 2007, 2009 GRIN3A NM_133445 1002 glutamate receptor, hsa-miR- >−0.01 0.87 2009 ionotropic, N-methyl- 4458 D-aspartate 3A PYGO2 NM_138300 1003 pygopus homolog 2 hsa-miR- −0.07 0.92 2005, (Drosophila) 4500 2007, 2009 DCAF15 NM_138353 1004 DDB1 and CUL4 hsa-miR- −0.17 0.95 2007, associated factor 15 4458 2009 MARS2 NM_138395 1005 methionyl-tRNA hsa-let-7d −0.37 0.94 2009 synthetase 2, mitochondrial MARCH9 NM_138396 1006 membrane-associated hsa-miR- −0.09 0.78 2007, ring finger (C3HC4) 9 4500 2009 ZNF689 NM_138447 1007 zinc finger protein hsa-miR- −0.29 0.94 2009 689 4500 CTHRC1 NM_138455 1008 collagen triple helix hsa-miR- −0.31 0.76 2009 repeat containing 1 4458 C11orf84 NM_138471 1009 chromosome 11 open hsa-miR- −0.14 0.94 2005, reading frame 84 4458 2007, 2009 H2AFV NM_138635 1010 H2A histone family, hsa-miR- >−0.03 <0.1 member V 4458 CD200R1 NM_138806 1011 CD200 receptor 1 hsa-let-7a −0.38 0.82 2009 ADAMTS15 NM_139055 1012 ADAM hsa-let-7i −0.38 >0.99 metallopeptidase with thrombospondin type 1 motif, 15 LIPH NM_139248 1013 lipase, member H hsa-miR- −0.29 0.94 2009 4500 PPTC7 NM_139283 1014 PTC7 protein hsa-let-7d −0.06 0.85 2007, phosphatase homolog 2009 (S. cerevisiae) GNAT1 NM_144499 1015 guanine nucleotide hsa-let-7g −0.14 <0.1 binding protein (G protein), alpha transducing activity polypeptide 1 CNOT6L NM_144571 1016 CCR4-NOT hsa-miR- −0.02 0.92 2007, transcription 4458 2009 complex, subunit 6- like MAPK1IP1L NM_144578 1017 mitogen-activated hsa-miR- −0.03 0.99 2009 protein kinase 1 4458 interacting protein 1- like TEX261 NM_144582 1018 testis expressed 261 hsa-miR- −0.04 0.8 2009 4458 FOPNL NM_144600 1019 FGFR1OP N-terminal hsa-let-7a −0.13 0.88 2009 like KLHL23 NM_144711 1020 kelch-like 23 hsa-let-7f −0.2 0.95 (Drosophila) SMCR8 NM_144775 1021 Smith-Magenis hsa-let-7d −0.16 0.95 2009 syndrome chromosome region, candidate 8 TSPEAR NM_144991 1022 thrombospondin-type hsa-let-7a −0.16 0.9 2005, laminin G domain and 2007 EAR repeats TET3 NM_144993 1023 tet oncogene family hsa-miR-98 −0.19 >0.99 2009 member 3 CCNY NM_145012 1024 cyclin Y hsa-let-7d −0.22 0.94 SLC2A12 NM_145176 1025 solute carrier family 2 hsa-miR- −0.2 0.93 2007, (facilitated glucose 4500 2009 transporter), member 12 B3GNT7 NM_145236 1026 UDP- hsa-miR- −0.2 0.98 GlcNAc:betaGal beta- 4458 1,3-N- acetylglucosaminyltransferase 7 KIFC2 NM_145754 1027 kinesin family hsa-miR- −0.16 0.64 member C2 4500 MTPN NM_145808 1028 myotrophin hsa-let-7d −0.04 0.82 2005, 2007, 2009 SYT11 NM_152280 1029 synaptotagmin XI hsa-miR- −0.13 0.98 2005, 4458 2007, 2009 POGLUT1 NM_152305 1030 protein O- hsa-let-7f −0.14 0.87 2007, glucosyltransferase 1 2009 GRPEL2 NM_152407 1031 GrpE-like 2, hsa-let-7i −0.18 0.93 2009 mitochondrial (E. coli) RNF165 NM_152470 1032 ring finger protein hsa-miR- −0.19 >0.99 2007, 165 4458 2009 ZNF362 NM_152493 1033 zinc finger protein hsa-miR- −0.08 0.98 2007, 362 4458 2009 ARL6IP6 NM_152522 1034 ADP-ribosylation-like hsa-miR- −0.33 0.83 factor 6 interacting 4500 protein 6 SLC16A14 NM_152527 1035 solute carrier family hsa-miR-98 −0.18 0.94 2007, 16, member 14 2009 (monocarboxylic acid transporter 14) C7orf60 NM_152556 1036 chromosome 7 open hsa-let-7a −0.06 0.87 2005, reading frame 60 2007, 2009 FAM116A NM_152678 1037 family with sequence hsa-miR- −0.08 0.7 similarity 116, 4458 member A SENP5 NM_152699 1038 SUMO1/sentrin hsa-miR- −0.17 0.94 2005, specific peptidase 5 4458 2007, 2009 HOXA9 NM_152739 1039 homeobox A9 hsa-let-7d −0.16 0.85 2005, 2007, 2009 SDK1 NM_152744 1040 sidekick homolog 1, hsa-miR- −0.14 0.95 cell adhesion 4458 molecule (chicken) SCUBE3 NM_152753 1041 signal peptide, CUB hsa-miR- >−0.02 0.88 2005, domain, EGF-like 3 4458 2007, 2009 RICTOR NM_152756 1042 RPTOR independent hsa-miR- −0.14 0.98 2007, companion of MTOR, 4500 2009 complex 2 YTHDF3 NM_152758 1043 YTH domain family, hsa-miR- −0.1 0.86 2005, member 3 4500 2007, 2009 MFSD8 NM_152778 1044 major facilitator hsa-miR-98 −0.33 0.91 superfamily domain containing 8 COL24A1 NM_152890 1045 collagen, type XXIV, hsa-let-7a −0.19 0.92 2005, alpha 1 2007, 2009 UHRF2 NM_152896 1046 ubiquitin-like with hsa-let-7d −0.41 0.89 2005, PHD and ring finger 2007, domains 2 2009 PXT1 NM_152990 1047 peroxisomal, testis hsa-let-7f −0.54 0.93 2009 specific 1 NPHP3 NM_153240 1048 nephronophthisis 3 hsa-let-7f −0.49 >0.99 2009 (adolescent) BRWD3 NM_153252 1049 bromodomain and hsa-let-7i −0.12 0.95 WD repeat domain containing 3 ATXN7L2 NM_153340 1050 ataxia 7-like 2 hsa-miR- −0.18 0.75 2007 4458 GPR26 NM_153442 1051 G protein-coupled hsa-miR- −0.17 0.95 2009 receptor 26 4500 LCORL NM_153686 1052 ligand dependent hsa-miR- −0.2 0.78 2007, nuclear receptor 4458 2009 corepressor-like FAM43A NM_153690 1053 family with sequence hsa-miR- −0.16 0.82 2009 similarity 43, member A 4458 TTL NM_153712 1054 tubulin tyrosine ligase hsa-miR- −0.08 0.94 2007, 4458 2009 ATP2A2 NM_170665 1055 ATPase, Ca++ hsa-miR- −0.28 0.96 2005, transporting, cardiac 4500 2007 muscle, slow twitch 2 IL28RA NM_170743 1056 interleukin 28 hsa-miR- −0.17 0.72 receptor, alpha 4458 (interferon, lambda receptor) RDH10 NM_172037 1057 retinol dehydrogenase hsa-miR-98 −0.19 0.95 2005, 10 (all-trans) 2007, 2009 DCUN1D3 NM_173475 1058 DCN1, defective in hsa-miR- −0.21 0.98 2007, cullin neddylation 1, 4500 2009 domain containing 3 (S. cerevisiae) LSM11 NM_173491 1059 LSM11, U7 small hsa-let-7b −0.35 0.94 2005, nuclear RNA 2007, associated 2009 SLC38A9 NM_173514 1060 solute carrier family hsa-miR- −0.17 0.82 2005, 38, member 9 4458 2007 KLHDC8B NM_173546 1061 kelch domain hsa-miR- −0.35 0.98 2009 containing 8B 4458 RFX6 NM_173560 1062 regulatory factor X, 6 hsa-let-7d −0.24 0.95 2005, 2007, 2009 PRR14L NM_173566 1063 proline rich 14-like hsa-miR- −0.03 0.9 4458 UBN2 NM_173569 1064 ubinuclein 2 hsa-miR- >−0.02 0.94 2009 4458 PGM2L1 NM_173582 1065 phosphoglucomutase hsa-miR- −0.05 >0.99 2005, 2-like 1 4458 2007, 2009 ANKRD52 NM_173595 1066 ankyrin repeat hsa-miR- >−0.06 0.96 2009 domain 52 4458 RIMKLA NM_173642 1067 ribosomal hsa-let-7b −0.08 <0.1 modification protein rimK-like family member A CCDC141 NM_173648 1068 coiled-coil domain hsa-miR- −0.17 0.95 containing 141 4458 SLC9A9 NM_173653 1069 solute carrier family 9 hsa-miR- −0.11 0.89 2005, (sodium/hydrogen 4458 2007, exchanger), member 9 2009 C3orf64 NM_173654 1070 chromosome 3 open hsa-let-7d −0.21 >0.99 2007, reading frame 64 2009 CRB2 NM_173689 1071 crumbs homolog 2 hsa-miR- −0.12 0.93 2009 (Drosophila) 4458 PRTG NM_173814 1072 protogenin hsa-miR-98 −0.56 >0.99 2007, 2009 SREK1IP1 NM_173829 1073 SREK1-interacting hsa-let-7g −0.12 0.95 2007, protein 1 2009 FAM84B NM_174911 1074 family with sequence hsa-miR- −0.13 0.58 2007 similarity 84, member B 4500 ZPLD1 NM_175056 1075 zona pellucida-like hsa-miR- −0.2 0.94 2009 domain containing 1 4458 TXLNA NM_175852 1076 taxilin alpha hsa-let-7b −0.1 0.9 2009 CHSY3 NM_175856 1077 chondroitin sulfate hsa-miR- −0.17 0.75 2007 synthase 3 4500 C19orf39 NM_175871 1078 chromosome 19 open hsa-let-7d −0.32 0.77 reading frame 39 ANKRD43 NM_175873 1079 ankyrin repeat hsa-miR- −0.22 0.94 2007, domain 43 4500 2009 FLJ36031 NM_175884 1080 hypothetical protein hsa-let-7g −0.31 0.88 2007, FLJ36031 2009 C5orf51 NM_175921 1081 chromosome 5 open hsa-miR- −0.26 0.94 2005, reading frame 51 4458 2007, 2009 PRR18 NM_175922 1082 proline rich 18 hsa-miR- −0.13 0.72 4500 CXorf36 NM_176819 1083 chromosome X open hsa-let-7e −0.02 0.81 reading frame 36 PDE12 NM_177966 1084 phosphodiesterase 12 hsa-let-7a −0.25 0.98 2007, 2009 SESTD1 NM_178123 1085 SEC14 and spectrin hsa-miR- −0.19 0.92 domains 1 4500 SNAI3 NM_178310 1086 snail homolog 3 hsa-let-7i −0.18 0.56 2007 (Drosophila) TMEM26 NM_178505 1087 transmembrane hsa-miR- −0.1 0.93 2009 protein 26 4458 NAT8L NM_178557 1088 N-acetyltransferase 8- hsa-miR-98 −0.05 0.94 like (GCN5-related, putative) RSPO2 NM_178565 1089 R-sporadin 2 hsa-let-7d −0.3 0.88 2007, 2009 MTDH NM_178812 1090 metadherin hsa-miR-98 −0.1 0.95 AGPAT6 NM_178819 1091 1-acylglycerol-3- hsa-let-7d −0.24 0.98 phosphate O- acyltransferase 6 (lysophosphatidic acid acyltransferase, zeta) MFSD4 NM_181644 1092 major facilitator hsa-let-7a −0.31 0.98 superfamily domain containing 4 TMTC3 NM_181783 1093 transmembrane and hsa-miR- −0.01 0.79 tetratricopeptide 4500 repeat containing 3 SLC46A3 NM_181785 1094 solute carrier family hsa-miR- −0.13 0.74 46, member 3 4500 USP12 NM_182488 1095 ubiquitin specific hsa-let-7f −0.37 0.9 peptidase 12 DDX26B NM_182540 1096 DEAD/H (Asp-Glu- hsa-let-7f −0.25 0.94 2009 Ala-Asp/His) box polypeptide 26B GDPD1 NM_182569 1097 glycerophosphodiester hsa-miR- −0.19 0.94 2005, phosphodiesterase 4458 2007, domain containing 1 2009 SP8 NM_182700 1098 Sp8 transcription hsa-miR- −0.16 0.92 2007, factor 4458 2009 ARRDC4 NM_183376 1099 arrestin domain hsa-miR- −0.15 0.94 2005, containing 4 4458 2007, 2009 KIF1B NM_183416 1100 kinesin family hsa-miR- −0.07 0.88 member 1B 4458 TMEM65 NM_194291 1101 transmembrane hsa-miR- −0.2 0.94 2007, protein 65 4500 2009 SLC16A9 NM_194298 1102 solute carrier family hsa-miR- −0.25 0.9 2009 16, member 9 4458 (monocarboxylic acid transporter 9) E2F6 NM_198256 1103 E2F transcription hsa-let-7c −0.21 0.98 2007, factor 6 2009 ANKRD46 NM_198401 1104 ankyrin repeat hsa-miR- −0.19 0.87 2009 domain 46 4458 NRK NM_198465 1105 Nik related kinase hsa-let-7i −0.07 0.94 2005, 2007, 2009 NHLRC2 NM_198514 1106 NHL repeat hsa-let-7d −0.08 0.83 containing 2 ZNF710 NM_198526 1107 zinc finger protein hsa-let-7d −0.24 >0.99 2003, 710 2007, 2009 TMEM110 NM_198563 1108 transmembrane hsa-miR- −0.24 0.94 2007, protein 110 4458 2009 RAB15 NM_198686 1109 RAB15, member hsa-miR- −0.16 0.94 2005, RAS onocogene 4458 2007, family 2009 DHX57 NM_198963 1110 DEAH (Asp-Glu-Ala- hsa-miR- −0.25 0.88 2005, Asp/His) box 4500 2007, polypeptide 57 2009 MED8 NM_201542 1111 mediator complex hsa-let-7f −0.42 0.92 subunit 8 ZNF784 NM_203374 1112 zinc finger protein hsa-miR- −0.21 0.83 2009 784 4458 PPAPDC2 NM_203453 1113 phosphatidic acid hsa-miR- −0.2 0.94 2007, phosphatase type 2 4500 2009 domain containing 2 SPRYD4 NM_207344 1114 SPRY domain hsa-miR- −0.2 0.94 2007, containing 4 4458 2009 FREM2 NM_207361 1115 FRAS1 related hsa-miR- −0.07 0.94 2009 extracellular matrix 4458 protein 2 C10orf140 NM_207371 1116 chromosome 10 open hsa-let-7d −0.13 0.85 2005, reading frame 140 2007, 2009

TABLE S3 3′ UTR sequences. Human FNTB 5′AGGACCTGGGTCCCGGCAGCTCTTTGCTCACCCATCTCCCCAGTCAGA CAAGGTTTATACGTTTCAATACATACTGCATTCTGTGCTACACAAGCCTT AGCCTCAGTGGAGCTGTGGTTCTCTTGGTACTTTCTTGTCAAACAAAACC AATGGCTCTGGGTTTGGAGAACACAGTGGCTGGTTTTAAAAATTCTTTCC ACACCTGTCAAACCAAAAATCTATCAGCCCACGTGGTGTGGTTGGTGAAC AGTGCATGCCAGGAGGAAGCAGTCCCTCCTCACCAGCTCTCCAGCCAGGA CGATCACACAGAGATGAATGGCATCTGAGTATTACGGCATCCAGAGCCAC TGCTGACTCCCACTTGCACGCCACCATTCAGTCACCAGACTGGGTGCCCT CCGATGGGTGGAATAAGTCTGCTTCATGCCAAGGCTGGGCTTTGGGTCCC ACCAAGATGAGTTCTCTGTAAGACTGTGGTGGAGTTGCACCAGGAGGTGC CTCTGCCTCTCGACTTGCACCCTGGTCATTTGTAAGGGAAAAGAGCTGGA GGTGGGGAGAGAAAGATCTCCTTCAGTTGGGAGTCCTTCCACTTCAACAC TGGAGAACTGAGCCTTGCATCTCTCCAGGGTCCAAGGCCACGCTTGGTGC ACAGGCAAGACTTGCTTCAGCCCCAGGTGTGGTGACTTAGACCTAGGAAA CCAATTATGAGTGGAAAGTGACCCTCTAGTTCAACTGTGCCAGAGGAAAC AGCCCTCCAGTGCCCACCTGCCTCACTCCTCCCTATCATGTACCGTGAAA ACCCCCTCTGATGGCCTCAAGGCAGTGCCTGCAGGCCGAGGCCCTTCTGG GGGTTTCTATCTTTCTTCCACCAGACTCCAAGCCCACTCTCCTCCAAGAC TGTGTTGTCTTTTCTCACCAAGAGTATTAACACTACTAAGTCTTTCACCT TAACTTATGACTCAGGATTTATTCACGTCCTGCCCACTCTAGGCTCACAG GAATAAAATCAAGTGCTAGACACACTGGCTGCTACTAAGGCACTAGCCTC TGTAGCTGGTGGTGGCAGCGTGGGGTGCCGCCCAGCGTGCTGGGTCCTGG CAGTGCCTCTGCTGTGCTGCACATTGAGCCCTTTCTCAGTCAGTGGAGTA TCAAGTTGGGCCATCTGTCTACTGACCTGGCCTTCATGTAAGCAGCTGTG GGCTGCGGGCAGACAGGAGCTCAGAGATGCAGCATGAGGCGCTTAGAAAA ACCTGGCCATTTGCTGCCTCTAATTCCCTTTTGCTTTG-3′ (SEQ ID NO: 1117) Zebrafish Fntb 5′ACTATCTATTTTTCAACTGTAAACATATTGGGGGATTTGGGCTAGCTT GAACTGTGCAGAGGAATCTTCTGTAAATGCTGTAGCCAAATGTCCTTTGC TGGTGTGTACAGCGTCTACAGATGGAGAAACACTCTGAGGCCTGATCTGC TGCTGCTTCAGCATGAGGTTATGGGTTTTAGCCAGGATAAACAGTAGAGA CTGACTAGGTAAGGTGTTTTTTCATGCACCAGTCATTGATTGATATTTTA TTGCACATGCCAGCTTATTTTGGGCAAAATGTTCCCAGAGTGTACGTGGC AGTGGGTTCTGGACAGAAATAAAGACTTGGATGGAAA-3′ (SEQ ID NO: 1118) Zebrafish Smarca5 5′GCAGGCAGGCATTTCACACACCTCACTCGGCGAGGAGCTTCAGTACAG CAATACTGCATTGATTGTTACGGGTCCCACTCATGTACTGTATGGATTTG CAGCACTGATCCTCGCCTCTCAAGTAGCTTGGCCTTCTTAACAAGGTGTA GAGTTGTAAATTAGGTCTCTTTTAGTTATATAATGTAACTACGGCTGTGC TGTCGGATGTGTTTTGTATTTATGGCTACTTCAAATTTTTTTTTGTACCA CATTCCATTTGCTTGTATCAGTTTAATTTGCAGTCTTTACCCCCTCATTA TTAGTGTCTTCAGTATTGTATTGTCTCTGTATCCGCCATTGGAAAGTGAC TAATAAATGTGGTTTTTATAAATGCTGCTCTGTATGTTTCCTACAAATAA ATGTAATGTCTTTTGCCTTGTA-3′ (SEQ ID NO: 1119)

TABLE S4 MiR mimics and antagomiR sequences. miRs used Sequence Dre-miR-100 mimic 5′-AACCCGUAGAUCCGAACUUGUG-3′ (SEQ ID NO: 1120) 5′-CAAGCUUGUAUCUAUAGGUAUC-3′ (SEQ ID NO: 1121) Dre-miR-99 mimic 5′-AACCCGUAGAUCCGAUCUUGUG-3′ (SEQ ID NO: 1122) 5′-CAAGCUCGAUUCUAUGGGUCUC-3′ (SEQ ID NO: 1123) Dre-miR-99 5′-ACAAGTTCGGATCTACGGGT-3′ inhibitor (SEQ ID NO: 1124) Dre-miR-100 5′-ACAAGATCGGATCTACGGGT-3′ inhibitor (SEQ ID NO: 1125) GFP siRNA (delivery 5′-GGCUACGUCCAGGAGCGCACC-3′ control) (SEQ ID NO: 1126) 5′-GGUGCGCUCCUGGACGUAGCC-3′-Cy5 (SEQ ID NO: 1127) Fntb morpholino 5′-GCGCCTCTTCCATGATGAGCTCTCA-3′ (translation- (SEQ ID NO: 1128) blocking) Smarca5 morpholino 5′-CTTCTTCCCGCTGCTGCTCCATGCT-3′ (translation- (SEQ ID NO: 1129) blocking) 

What is claimed is:
 1. A method of modulating proliferation of a cardiomyocyte, comprising: (i) introducing into a cardiomyocyte a nucleic acid encoding an antagonist of a micro RNA (miR) 99 micro RNA, a nucleic acid encoding an antagonist of a miR 100 micro RNA, and a nucleic acid encoding an antagonist of a let-7a micro RNA, and a nucleic acid encoding an antagonist of a let-7c micro RNA, thereby forming a transfected cardiomyocyte; and (ii) allowing the transfected cardiomyocyte to divide, thereby modulating proliferation of the cardiomyocyte.
 2. The method of claim 1, wherein the introducing comprises transfecting the cardiomyocyte with a) a lentiviral vector or an adeno-associated viral (AAV) vector comprising the nucleic acid encoding the antagonist of the miR 99 micro RNA and the nucleic acid encoding the antagonist of the miR 100 micro RNA, and b) a lentiviral vector or an AAV vector encoding the nucleic acid encoding the antagonist of the let-7a micro RNA and the antagonist of the let-7c micro RNA.
 3. The method of claim 1, wherein the proliferation of the cardiomyocyte is increased compared to a control cardiomyocyte lacking the nucleic acid encoding the antagonist of the miR 99 micro RNA, the nucleic acid encoding the antagonist of the miR 100 micro RNA, the nucleic acid encoding the antagonist of the let-7a micro RNA, and the, and a nucleic acid encoding the antagonist of a let-7 c micro RNA.
 4. A method of modulating proliferation of a cardiomyocyte, said method comprising: (i) contacting a cardiomyocyte with a small molecule that modulates expression or activity of a miR 99 micro RNA-regulated protein, a small molecule that modulates expression or activity of a miR 100 micro RNA-regulated protein, a small molecule that modulates expression or activity of a let-7a micro RNA -regulated protein, and small molecule that modulates expression or activity of a let-7c micro RNA regulated protein, thereby forming a treated cardiomyocyte; and (ii) allowing said treated cardiomyocyte to divide, thereby modulating proliferation of said cardiomyocyte.
 5. The method of claim 4, wherein said proliferation of said cardiomyocyte is increased compared to a control cardiomyocyte lacking said small molecule.
 6. The method of claim 4, wherein the small molecule that modulates expression or activity of the miR 99 mirco RNA-regulated protein, the small molecule that modulates expression or activity of the miR 100 micro RNA-regulated protein, the small molecule that modulates expression or activity of the let-7a micro RNA -regulated protein, and/or the small molecule that modulates expression or activity of the let-7c micro RNA regulated protein is a synthetic micro RNA molecule.
 7. The method of claim 4, comprising contacting the cardiomyocyte with a nucleic acid molecule comprising the nucleic acid sequence as set forth in SEQ ID NO:1124 or SEQ ID NO:1125.
 8. The method of claim 1, further comprising measuring the proliferation of the cardiomyocyte.
 9. The method of claim 4, wherein the proliferation of the cardiomyocyte is increased.
 10. The method of claim 1, wherein the cardiomyocyte is in vivo.
 11. The method of claim 1, wherein the cardiomyocyte is in vitro.
 12. The method of claim 2, wherein a) the lentiviral vector or the AAV vector comprising the nucleic acid encoding the antagonist of the mir 99 micro RNA and the antagonist of the mir 100 micro RNA, and b) the lentiviral vector or the AAV vector encoding the nucleic acid encoding the antagonist of the let-7a micro RNA and the antagonist of the let-7c micro RNA are the same vector.
 13. The method of claim 2, wherein a) the lentiviral vector or the AAV vector comprising the nucleic acid encoding the antagonist of the mir 99 micro RNA and the antagonist of the mir 100 micro RNA, and b) the lentiviral vector or the AAV vector encoding the nucleic acid encoding the antagonist of the let-7a are different vectors.
 14. The method of claim 1, comprising transfecting the cardiomycocyte with a nucleic acid comprising the nucleic acid sequence set forth as SEQ ID NO:
 1124. 15. The method of claim 1, comprising transfecting the cardiomycocyte with a nucleic acid comprising the nucleic acid sequence set forth as SEQ ID NO:
 1125. 